The present invention relates to novel selective human NK3 receptor antagonist compounds for the preparation of drugs useful in the treatment of psychiatric diseases, diseases of psychosomatic origin, hypertension and, in general, any central or peripheral pathological condition in which neurokinin B and the NK3 receptor are involved in the interneuronal regulatory processes, to a method of obtaining said compounds and to the pharmaceutical compositions in which they are present as the active principle.
Diseases of psychosomatic origin are understood as meaning diseases which originate in the central nervous system (CNS) and have pathological consequences on the peripheral nervous system.
In recent years, numerous research studies have been carried out on tachykinins and their receptors. Tachykinins are distributed throughout both the central nervous system and the peripheral nervous system. The tachykinin receptors have been recognized and are classified into three types: NK1, NK2, NK3. Substance P (SP) is the endogenous ligand of the NK1 receptors, neurokinin A (NKA) that of the NK2 receptors and neurokinin B (NKB) that of the NK3 receptors.
The NK1, NK2 and NK3 receptors have been identified in different species. Thus the NK3 receptors have been identified in the guinea-pig, the rat and the monkey (Br. J. Pharmacol., 1990, 99, 767-773); Neurochem. Int., 1991, 18 149-165); they have also been identified in man (FEBS Letters, 1992, 299 (1), 90-95).
A review by C. A. Maggi et al. looks at the tachykinin receptors and their antagonists and gives an account of the pharmacological studies and the applications in human therapeutics (J. Autonomic Pharmacol., 1993, 13, 23-93).
The following non-peptide compounds may be mentioned among the specific NK1 receptor antagonists: CP-96345 (J. Med. Chem., 1992, 35, 2591-2600), RP-68651 (Proc. Natl. Acad. Sci. USA, 1991, 88, 10208-10212) and SR 140333 (Curr. J. Pharmacol., 1993, 250, 403-413).
In the case of the NK2 receptor, the non-peptide selective antagonist SR 48968 has been described in detail (Life Sci., 1992, 50, PL101-PL106).
As far as the human NK3 receptor is concerned, the non-peptide selective antagonist (+)-N-[1-[3-[1-benzoyl-3-(3,4-dichlorophenyl)piperid-3-yl]propyl]-4-phenylpiperid-4-yl]-N-methylacetamide hydrochloride, or SR 142801, has been described (EP-A-0 673 928; Peptides and their antagonists in tissue injury, Montreal, Canada, Jul. 31, 1994-Aug. 3, 1994. Canadian J. Physiol. Pharmacol., 1994, 72 (suppl. 2), 25, Abst. III. 0.9; Life Sci., 1994, 56 (1), 27-32; British Pharmacol. Society, Canterbury, Apr. 6-8, 1995; Eur. J. Pharmacol., 1995, 278 (1), 17-25; 1st Eur. Congress Pharmacol., Milan, Jun. 16-19, 1995).
Patent applications EP 474 561 and EP 512 901 describe neurokinin antagonists, more particularly NK1 or NK2 receptor antagonists. Pharmacological studies of peptide and non-peptide NK1 and NK2 receptor antagonists have shown that their affinities for these receptors, and their pharmacological activities, are very dependent on the species; this is very probably the result of small differences in the amino acid sequences, inducing very slight structural variations in these receptors from one species to another (J. Autonomic Pharmacol., 1993, 13 23-93). Some experimental data, confirmed by pharmacological characterization of the compounds forming the subject of the present invention, seem to indicate that a comparable situation exists for the NK3 receptor. In particular, the human NK3 receptor differs from the NK3 receptor of the rat.
Non-peptide compounds have now been found which have a very strong affinity for the human NK3 receptor and a high specificity for said receptor. These compounds can be used for the preparation of drugs useful in the treatment of psychiatric diseases, diseases of psychosomatic origin and any central or peripheral diseases in which neurokinin B and the NK3 receptor are involved in the interneuronal regulatory processes.
Very strong affinity for the human NK3 receptor is understood as meaning an affinity characterized by an inhibition constant Ki which is generally less than 5.10xe2x88x929 M.
In ligand binding studies, the inhibition constant Ki is defined by the Cheng-Prusoff relationship (in Receptor Binding in Drug Research, eds. R. A. O""BRIEN. Marcel Dekker, New York, 1986):   Ki  =            IC      50              1      +                        [          L          ]                Kd            
[L]: concentration of the ligand,
Kd: dissociation constant of the ligand,
IC50: concentration which inhibits ligand binding by 50%.
High specificity for the human NK3 receptor is understood as meaning that the inhibition constant (Ki) for the human NK3 receptor is generally at least 100 times lower than the inhibition constant (Ki) for the NK2 receptor or the inhibition constant for the NK1 receptor of different species.
Thus, according to one of its aspects, the present invention relates to compounds of the formula 
in which:
R1 is hydrogen;
R2 is the methyl group;
or R1 and R2 together form a group xe2x80x94(CH2)3xe2x80x94 or xe2x80x94(CH2)4xe2x80x94;
Ar1 is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C1-C4)alkoxy, a (C1-C4)alkyl, a trifluoromethyl and a methylenedioxy, said substituents being identical or different; a thienyl which is unsubstituted or substituted by a halogen atom; a benzothienyl which is unsubstituted or substituted by a halogen atom; a naphthyl which is unsubstituted or substituted by a halogen atom; an indolyl which is unsubstituted or N-substituted by a (C1-C4)alkyl or a benzyl; an imidazolyl which is unsubstituted or substituted by a halogen atom; a pyridyl which is unsubstituted or substituted by a halogen atom; or a biphenyl;
T is a group xe2x80x94CH2xe2x80x94; a group xe2x80x94COxe2x80x94; a group xe2x80x94COOxe2x80x94; or a group xe2x80x94CONR3xe2x80x94 in which R3 is a hydrogen or a (C1-C4)alkyl;
A is a direct bond; a group xe2x80x94(CH2)txe2x80x94, in which t is one, two or three; or a vinylene group;
or xe2x80x94Txe2x80x94Axe2x80x94 is the group xe2x80x94SO2xe2x80x94;
Z is an optionally substituted, mono-, di- or tri-cyclic aromatic or heteroaromatic group; and
B is:
ixe2x80x94either a group B1 of the formula 
in which J1 is:
i1 either a group 
in which:
x is zero or one;
Ar2 is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a nitro, a hydroxyl, a trifluoromethyl, a (C1-C4)alkyl, a (C1-C4)alkoxy and a methylenedioxy, said substituents being identical or different; a pyridyl; a thienyl; a pyrimidyl; or an imidazolyl which is unsubstituted or substituted by a (C1-C4)alkyl; and
X1 is a group selected from:
(1) hydrogen;
(2) (C1-C7)alkyl;
(3) formyl;
(4) (C1-C7)alkylcarbonyl;
(5) xe2x80x94(CH2)mxe2x80x94OR4;
(6) xe2x80x94(CH2)mxe2x80x94OCOR5;
(7) xe2x80x94(CH2)mxe2x80x94OCONHxe2x80x94(C1-C7)alkyl;
(8) xe2x80x94Oxe2x80x94CH2CH2xe2x80x94OR6;
(9) xe2x80x94(CH2)nxe2x80x94SR7;
(10) xe2x80x94CH2xe2x80x94S(O)jxe2x80x94(C1-C7)alkyl;
(11) xe2x80x94NR8R9;
(12) xe2x80x94(CH2)pxe2x80x94NR10R11;
(13) xe2x80x94NR12COR13;
(14) xe2x80x94NR4COCOR15;
(15) xe2x80x94(CH2)pxe2x80x94NR14C(xe2x95x90W1)R16;
(16) xe2x80x94(CH2)mxe2x80x94NR14COOR17;
(17) xe2x80x94(CH2)mxe2x80x94NR14SO2R18;
(18) xe2x80x94(CH2)mxe2x80x94NR14C(xe2x95x90W1)NR19R20;
(19) xe2x80x94(CH2)nxe2x80x94COOR21;
(20) xe2x80x94(CH2)nxe2x80x94C(xe2x95x90W1)NR19R20;
(21) xe2x80x94COxe2x80x94NR22xe2x80x94NR23R24;
(22) xe2x80x94CN; 
xe2x80x83or X1 forms a double bond between the carbon atom to which it is bonded and the adjacent carbon atom of the piperidine ring;
in which groups:
m is zero, one or two;
n is zero or one;
p is one or two;
j is one or two;
W1 is an oxygen atom or a sulfur atom;
R4 is a hydrogen or a (C1-C7)alkyl;
R5 is a hydrogen; a (C1-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; or a pyridyl;
R6 is a hydrogen; a (C1-C7)alkyl; a formyl; or a (C1-C7)alkylcarbonyl;
R7 is a hydrogen or a (C1-C7)alkyl;
R8 and R9 are each independently a hydrogen or a (C1-C7)alkyl; R9 can also be a (C3-C7)cycloalkylmethyl, a benzyl or a phenyl;
or R8 and R9, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
R10 and R11 are each independently a hydrogen or a (C3-C7)alkyl; R11 can also be a (C3-C7)cycloalkylmethyl or a benzyl;
R12 is a hydrogen or a (C1-C7)alkyl;
R13 is a hydrogen; a (C1-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl;
or R12 and R13 together are a group xe2x80x94(CH2)uxe2x80x94, in which u is three or four;
R14 is a hydrogen or a (C1-C7)alkyl;
R15 is a (C1-C4)alkoxy;
R16 is a hydrogen; a (C1-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl;
R17 is a (C1-C7)alkyl or a phenyl;
R18 is a (C1-C7)alkyl; an amino which is free or substituted by one or two (C1-C7)alkyls; or a phenyl which is unsubstituted or monosubstituted or poly-substituted by a substituent selected from a halogen atom, a (C1-C7)alkyl, a trifluoromethyl, a hydroxyl, a (C1-C7)alkoxy, a carboxyl, a (C1-C7)alkoxycarbonyl, a (C1-C7)alkylcarbonyloxy, a cyano, a nitro and an amino which is free or substituted by one or two (C1-C7)alkyls, said substituents being identical or different;
R19 and R20 are each independently a hydrogen or a (C1-C7)alkyl; R20 can also be a (C3-C7)cycloalkyl; a (C3-C7)cycloalkylmethyl; a hydroxyl; a (C1-C4)alkoxy; a benzyl; a phenyl; or a (C1-C7)alkyl substituted by a hydroxyl, a (C1-C3)alkoxy, a phenyl, a carboxyl, a (C1-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (C1-C7)alkyls;
or R19 and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
R21 is a hydrogen or a (C1-C7)alkyl;
R22 is a hydrogen or a (C1-C7)alkyl;
R23 and R24 are each independently a hydrogen or a (C1-C7)alkyl;
R25 is a hydrogen or a (C1-C7)alkyl; and
R26 and R27 are each independently a hydrogen or a (C1-C7)alkyl; R27 can also be a formyl or a (C1-C7)alkylcarbonyl; 
in which Ar2 is as defined above; 
in which Ar2 is as defined above; 
in which Ar2 is as defined above; 
in which:
Ar2 is as defined above;
Am1 is an amino group substituted by two (C1-C4)alkyls; and
r is two or three; 
in which:
Ar2 is as defined above;
W2 is an oxygen atom; a sulfur atom; a sulfinyl; a sulfonyl; or a group xe2x80x94NL1xe2x80x94;
L1 is a hydrogen; a (C1-C4)alkyl; a (C1-C4)alkylcarbonyl; or a group xe2x80x94(CH2)vxe2x80x94 Am2;
v is one, two or three; and
Am2 is an amino group which is unsubstituted or monosubstituted or disubstituted by a (C1-C4)alkyl; Am2 can also be a pyrrolidino, piperidino or morpholino group;
iixe2x80x94or a group B2 of the formula 
in which J2 is: 
in which:
Ar2 is as defined above;
r is two or three; and
Am1 is as defined above;
iiixe2x80x94or a group B3 of the formula 
in which J3 is: 
in which:
W3 is an oxygen atom; a sulfur atom; or a group NR30, in which R30 is a hydrogen or a (C1-C3)alkyl;
R28 is a hydrogen; a (C1-C6)alkyl; a (C3-C6)alkenyl in which one vinylic carbon atom is not bonded to the nitrogen atom; a 2-hydroxyethyl; a (C3-C7)cycloalkyl; a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a trifluoromethyl, a (C1-C4)alkyl, a (C1-C4)alkoxy, a nitro, an amino and a hydroxyl, said substituents being identical or different; or a 6-membered heteroaryl containing one or two nitrogen atoms as heteroatoms, said heteroaryl being unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a trifluoromethyl, a (C1-C4)alkyl, a (C1-C4)alkoxy, a nitro, an amino and a hydroxyl, said substituents being identical or different;
R29 is a hydrogen; a (C1-C6)alkyl which is unsubstituted or substituted by a hydroxyl and/or by one, two or three fluorine atoms; a (C3-C6)cycloalkyl; a (C1-C5)alkoxy (only when W3 is an oxygen atom); a (C3-C6)cycloalkoxy (only when W3 is an oxygen atom); or a group xe2x80x94NR31R32 containing from zero to seven carbon atoms, R29 being other than an unsubstituted (C1-C4)alkyl when simultaneously W3 is an oxygen and R28 is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a nitro, a hydroxyl, a trifluoromethyl, a (C1-C4)alkyl and a (C1-C4)alkoxy, said substituents being identical or different; a pyridyl; or a pyrimidyl;
or R28 and R29 together form a divalent hydrocarbon group L2, in which the 1-position is bonded to the carbon atom carrying the substituent W3, the divalent hydrocarbon group L2 being selected from a trimethylene, a cis-propenylene, a tetramethylene, a cis-butenylene, a cis,cis-butadienylene, a pentamethylene and a cis-pentenylene, said divalent hydrocarbon group L2 being unsubstituted or substituted by one or two methyls; and
R31 and R32 are each independently a hydrogen, a (C1-C5)alkyl or a (C3-C6)cycloalkyl; or R31 and R32, together with the nitrogen atom to which they are bonded, form a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine (or its S-oxide) and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
ivxe2x80x94or a group B4 of the formula 
in which:
W4 is a (C1-C8)alkyl or a (C3-C8)cycloalkyl, said alkyl and cycloalkyl groups being unsubstituted or substituted by one or more substituents selected from a halogen atom; a (C3-C6)cycloalkyl; a cyano; a nitro; a hydroxyl; a (C1-C4)alkoxy; a formyloxy; a (C1-C4)alkylcarbonytoxy; an arylcarbonyl; a heteroarylcarbonyl; an oxo; an imino which is unsubstituted or substituted on the nitrogen atom by a (C1-C6)alkyl, a (C3-C6)cycloalkyl, a formyl, a (C1-C4)alkylcarbonyl or an arylcarbonyl; a hydroxyimino which is unsubstituted or substituted on the oxygen atom by a (C1-C4)alkyl or a phenyl; a group xe2x80x94NR33R34 containing from zero to seven carbon atoms; a group xe2x80x94NR35R36; a group xe2x80x94C(xe2x95x90NR37)NR38R39, in which the group xe2x80x94NR38R39 contains from zero to seven carbon atoms; and a group xe2x80x94CON(OR40)R41, said substituents being identical or different;
R33 and R34 are each independently a hydrogen, a (C1-C5)alkyl or a (C3-C6)cycloalkyl; or R33 and R34, together with the nitrogen atom to which they are bonded, form a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine (or its S-oxide) and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
R35 is a hydrogen or a (C1-C4)alkyl;
R36 is a formyl; a (C1-C4)alkylcarbonyl; an arylcarbonyl; a heteroarylcarbonyl; or a group xe2x80x94C(xe2x95x90W5)NR38R39, in which the group xe2x80x94NR38R39 contains from zero to seven carbon atoms;
W5 is an oxygen atom; a sulfur atom; a group NR37; or a group CHR42;
R37 is a hydrogen or a (C1-C4)alkyl; or R37 and R39 together form an ethylene group or a trimethylene group;
R38 and R39 are each independently a hydrogen, a (C1-C5)alkyl or a (C3-C6)cycloalkyl; or R38 and R39, together with the nitrogen atom to which they are bonded, form a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine (or its S-oxide) and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl; or R38 is a hydrogen or a (C1-C4)alkyl and R39 and R37 together form an ethylene group or a trimethylene group;
R40 and R41 are each independently a (C1-C3)alkyl;
R42 is a cyano; a nitro; or a group SO2R43,
R43 is a (C1-C4)alkyl or a phenyl; and when W4 is a cyclic group or when a substituent of W4 is a cyclic group or contains a cyclic group, said cyclic groups can also be substituted on a carbon atom by one or more (C1-C3)alkyls; and when a substituent of W4 contains an aryl group or a heteroaryl group, said aryl or heteroaryl groups can also be monosubstituted or polysubstituted by a substituent selected from a halogen atom, a (C1-C4)alkyl, a (C1-C4)alkoxy, a cyano, a trifluoromethyl and a nitro, said substituents being identical or different;
vxe2x80x94or a group B5 of the formula 
in which:
W6 and W7 are each a hydrogen; or W6 is a hydrogen and W7 is a hydroxyl;
W8 is an aryl or a heteroaryl which are unsubstituted or substituted by an aryl, an arylcarbonyl, a heteroaryl or a heteroarylcarbonyl; said aryl or heteroaryl groups can also be monosubstituted or polysubstituted on the aromatic or heteroaromatic moiety and on a carbon atom by a substituent selected from a halogen atom; a cyano; a trifluoromethyl; a nitro; a hydroxyl; a (C1-C5)alkoxy; a formyloxy; a (C1-C4)alkylcarbonyloxy; a group xe2x80x94NR33R34 containing from zero to seven carbon atoms; a group xe2x80x94NR35R36; a group xe2x80x94C(xe2x95x90NR37)NR38R39, in which the group xe2x80x94NR38R39 contains from zero to seven carbon atoms; a group xe2x80x94COOR44; a group xe2x80x94CONR45R46, in which the group NR45R46 contains from zero to seven carbon atoms; a mercapto; a group xe2x80x94S(O)SR47; a (C1-C5)alkyl; a formyl; and a (C1-C4)alkylcarbonyl, said substituents being identical or different; when W6 and W7 are each a hydrogen, W8 is other than a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a nitro, a hydroxyl, a trifluoromethyl and a (C1-C4)alkoxy, said substituents being identical or different; a pyridyl; a thienyl; a pyrimidyl; or an imidazolyl which is unsubstituted or substituted by a (C1-C4)alkyl;
or W7 is a hydrogen and W6 and W8, together with a diradical W9 and the piperidine carbon atom to which they are bonded, form a spiro ring in which W8 is a phenyl substituted in the ortho position by a diradical W9, which is itself joined to W6, said phenyl being unsubstituted or substituted by a substituent selected from a halogen atom, a (C1-C3)alkyl, a (C1-C3)alkoxy, a hydroxyl, a (C1-C3)alkylthio, a (C1-C3)alkylsulfinyl and a (C1-C3)alkylsulfonyl; the diradical W9 is a methylene, a carbonyl or a sulfonyl; and W6 is an oxygen atom or a group xe2x80x94NR48xe2x80x94, in which R48 is a hydrogen or a (C1-C3)alkyl;
R33, R34, R35, R36, R37, R38 and R39 are as defined above for the group B4;
R44 is a hydrogen; a (C1-C5)alkyl; an aryl; a heteroaryl; an arylmethyl; or a heteroarylmethyl;
R45 and R46 are each independently a hydrogen, a (C1-C5)alkyl or a (C3-C6)cycloalkyl; or R45 and R46, together with the nitrogen atom to which they are bonded, form a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine (or its S-oxide) and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
s is zero, one or two;
R47 is a (C1-C6)alkyl; a (C3-C6)cycloalkyl; an aryl; or a heteroaryl; and when W8 or a substituent of W8 contains a cyclic group, said cyclic group can also be substituted by one or more methyls; and when a heteroaryl group forming part of W8 or of a substituent of W8 contains a nitrogen atom as the heteroatom, said nitrogen atom can also be substituted by a (C1-C5)alkyl; and when W8 or a substituent of W8 contains a (C1-C5)alkyl, (C1-C5)alkoxy, formyl or (C1-C4)-alkylcarbonyl group, said (C1-C5)alkyl, (C1-C5)alkoxy, formyl or (C1-C4)alkylcarbonyl groups can also be substituted by a hydroxyl, a (C1-C3)alkoxy or one or more halogen atoms, with the proviso that a carbon atom bonded to a nitrogen atom or to an oxygen atom is not substituted by a hydroxyl or an alkoxy group, and with the proviso that a carbon atom in the xcex1-position of a (C1-C4)alkylcarbonyl group is not substituted by a chlorine, bromine or iodine atom;
vixe2x80x94or a group B6 of the formula 
in which J4 is: 
in which:
W10 is a phenyl which is unsubstituted or monosubstituted to trisubstituted by a substituent selected from a halogen atom, a (C1-C6)alkoxy, a (C1-C6)alkyl and a trifluoromethyl, said substituents being identical or different; a benzyl which is unsubstituted or monosubstituted to trisubstituted by a substituent selected from a halogen atom, a (C1-C6)alkoxy, a (C1-C6)alkyl and a trifluoromethyl, said substituents being identical or different; a naphthyl which is unsubstituted or monosubstituted to trisubstituted by a substituent selected from a halogen atom, a (C1-C6)alkoxy, a (C1-C6)alkyl and a trifluoromethyl, said substituents being identical or different; a pyridyl which is unsubstituted or monosubstituted or disubstituted by a substituent selected from a halogen atom, a (C1-C6)alkyl and a (C1-C6)alkoxy, said substituents being identical or different; a thienyl; a pyrimidyl; or an imidazolyl; and 
in which:
R50 is a hydrogen, a (C1-C6)alkyl or a benzyl; and
R51 is from one to three substituents selected from a hydrogen, a halogen atom, a trifluoromethyl, a (C1-C6)alkyl and a (C1-C6)alkoxy, said substituents being identical or different;
viixe2x80x94or a group B7 of the formula 
in which:
f and g are each independently zero, one, two, three, four or five, with the proviso that f+g is equal to one, two, three, four or five;
W12 is a direct bond; a (C1-C3)alkylene which is unsubstituted or substituted by an oxo, a group OR52, a halogen, a trifluoromethyl or a phenyl which is itself unsubstituted or mono-, di- or tri-substituted by a substituent selected from a hydroxyl, a cyano, a halogen and a trifluoromethyl; a group xe2x80x94S(O)kxe2x80x94; a group (C1-C3)alkylene-S(O)kxe2x80x94; a group xe2x80x94S(O)kxe2x80x94(C1-C2)alkylene; a group xe2x80x94S(O)kxe2x80x94NHxe2x80x94; a group xe2x80x94S(O)jxe2x80x94NR52xe2x80x94; a group xe2x80x94S(O)jxe2x80x94NR52xe2x80x94(C1-C2)alkylene; a group xe2x80x94CONR52xe2x80x94; a group xe2x80x94CONR52xe2x80x94(C1-C2)alkylene; a group xe2x80x94COOxe2x80x94; or a group xe2x80x94COOxe2x80x94(C1-C2)alkylene;
W13 is a group xe2x80x94NR53xe2x80x94; an oxygen atom; a sulfur atom; a sulfinyl; or a sulfonyl, with the proviso that when W12 is a direct bond and when W14 is a (C1-C3)alkylene, W13 is a group xe2x80x94NR53xe2x80x94;
W14 is a direct bond; a (C1-C3)alkylene which is unsubstituted or substituted by an oxo, a group OR52, a halogen, a trifluoromethyl or a phenyl which is itself unsubstituted or mono-, di- or tri-substituted by a substituent selected from a group OR52, a halogen and a trifluoromethyl; a group xe2x80x94S(O)kxe2x80x94; a group (C1-C3)alkylene-S(O)kxe2x80x94; a group xe2x80x94S(O)kxe2x80x94(C1-C2)alkylene; a group xe2x80x94NHS(O)jxe2x80x94; a group xe2x80x94NHxe2x80x94(C1-C2)alkylene-S(O)jxe2x80x94; a group xe2x80x94S(O)jNR52xe2x80x94; a group xe2x80x94S(O)jxe2x80x94NR52xe2x80x94(C1-C2)alkylene; a group xe2x80x94NHCOxe2x80x94(C1-C2)alkylene; a group xe2x80x94NR52xe2x80x94COxe2x80x94; a group xe2x80x94NR52xe2x80x94(C1-C2)alkylene-COxe2x80x94; a group xe2x80x94OCOxe2x80x94; or a group (C1-C2)alkylene-OCOxe2x80x94;
W15-W16 together form two adjacent atoms of a cyclic radical of the formula 
said cyclic radical being a phenyl, a naphthyl or a heteroaryl group selected from a benzimidazolyl, a benzofuranyl, a benzoxazolyl, a furanyl, an imidazolyl, an indolyl, an isoxazolyl, an isothiazolyl, an oxadiazolyl, an oxazolyl, a pyrazinyl, a pyrazolyl, a pyridyl, a pyrimidyl, a pyrrolyl, a quinolyl, a tetrazolyl, a thiadiazolyl, a thiazolyl, a thienyl and a triazolyl, and said phenyl, naphthyl or heteroaryl cyclic radical being unsubstituted or mono-, di- or tri-substituted by R54;
k is zero, one or two;
j is one or two;
R52 is a hydrogen; a (C1-C6)alkyl which is unsubstituted or monosubstituted or disubstituted by a substituent selected independently from a hydroxyl, an oxo, a cyano, a halogen atom, a trifluoromethyl and a phenyl which is itself unsubstituted or substituted by a hydroxyl, a (C1-C3)alkyl, a cyano, a halogen, a trifluoromethyl or a (C1-C4)alkoxy; a phenyl, a pyridyl or a thiophene, said phenyl, pyridyl or thiophene being unsubstituted or mono-, di- or tri-substituted by a substituent selected independently from a hydroxyl, a (C1-C4)alkyl, a cyano, a halogen atom and a trifluoromethyl; or a (C1-C3)alkoxy;
R53 is a hydrogen; a (C1-C8)alkyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a group xe2x80x94OR52, an oxo, a group xe2x80x94NHCOR52, a group xe2x80x94NR55R56, a cyano, a halogen atom, a trifluoromethyl and a phenyl which is itself unsubstituted or substituted by a hydroxyl, a cyano, a halogen atom or a trifluoromethyl; a group xe2x80x94S(O)R57; a group xe2x80x94CO2R57; a group xe2x80x94SO2R57; a group xe2x80x94COR57; or a group xe2x80x94CONR56R57;
R54 is a hydrogen; a (C1-C6)alkyl which is unsubstituted or monosubstituted or disubstituted by a hydrogen or a hydroxyl; an oxo; a group xe2x80x94OR52; a halogen atom; a trifluoromethyl; a nitro; a cyano; a group xe2x80x94NR55R56; a group xe2x80x94NR55COR56; a group xe2x80x94NR55CO2R56; a group xe2x80x94NHS(O)jR52; a group xe2x80x94NR55S(O)jR56; a group xe2x80x94CONR55R56; a group xe2x80x94COR52; a group xe2x80x94CO2R52; a group xe2x80x94S(O)jR52; or a heteroaryl group, said heteroaryl being selected from a benzimidazolyl, a benzofuranyl, a benzoxazolyl, a furanyl, an imidazolyl, an indolyl, an isoxazolyl, an isothiazolyl, an oxadiazolyl, an oxazolyl, a pyrazinyl, a pyrazolyl, a pyridyl, a pyrimidinyl, a pyrrolyl, a quinolyl, a tetrazolyl, a thiadiazolyl, a thiazolyl, a thienyl and a triazolyl, and said heteroaryl being unsubstituted or monosubstituted or disubstituted by R58;
R55 is R52;
R56 is R52;
or R55 and R56, together with the atoms to which they are bonded, form a five-, six- or seven-membered, saturated monocyclic heterocycle containing one or two heteroatoms, said heteroatoms being selected independently from a nitrogen atom, an oxygen atom and a sulfur atom, said heterocycle being unsubstituted or monosubstituted or disubstituted by a substituent selected from a hydroxyl, an oxo, a cyano, a halogen atom and a trifluoromethyl;
R57 is a (C1-C6)alkyl which is unsubstituted or mono-, di- or tri-substituted by a substituent selected from a hydroxyl, an oxo, a cyano, a group xe2x80x94OR52, a group xe2x80x94NR55R56, a group xe2x80x94NR55COR56, a halogen atom, a trifluoromethyl and a phenyl which is itself unsubstituted or mono-, di- or tri-substituted by a substituent selected from a hydroxyl, an oxo, a cyano, a group xe2x80x94NHR52, a group xe2x80x94NR55R56, a group xe2x80x94NR55COR56, a halogen atom, a trifluoromethyl and a (C1-C3)alkyl;
R58 is a hydrogen; a (C1-C6)alkyl which is unsubstituted or monosubstituted or disubstituted by a hydrogen or a hydroxyl; an oxo; a group xe2x80x94OR52; a trifluoromethyl; a nitro; a cyano; a group xe2x80x94NR55R56; a group xe2x80x94NR55COR56; a group xe2x80x94NR55CO2R56; a group xe2x80x94NHS(O)jR52; a group xe2x80x94NR55S(O)jR56; a group xe2x80x94CONR55R56; a group xe2x80x94COR52; a group xe2x80x94CO2R52; a group xe2x80x94S(O)jR52; or a phenyl, and the group B7 being other than the group B5 when W7 is a hydrogen and W6 and W8, together with a diradical W9 and the piperidine carbon atom to which they are bonded, form a spiro ring;
viiixe2x80x94or a group B8 of the formula 
in which:
W17 is a direct bond; a double bond; or a divalent hydrocarbon radical;
W18 is a radical which is joined to the carbon atom of the heterocycle either by a single bond when W17 is a double bond, or by a double bond in the other cases;
W19 is an unsubstituted or optionally substituted heteroatom;
W20 is a hydrocarbon radical of which the 1-position is joined to W19; and
the meanings of W17, W18, W19 and W20 are selected from:
(a) W17 is a direct bond; W18 is an oxo or thioxo group; W19 is an oxy or thio group or a group NR59; and W20 is a hydrocarbon radical L3; or
(b) W17 is a direct bond; W18 is a group NR60; W19 is a group NR61; and W20 is a hydrocarbon radical L3; or
(c) W17 is a double bond; W18 is a group OR61, SR61 or NR62R63; W19 is a nitrogen atom; and W20 is a hydrocarbon radical L3; or
(d) W17 is a methylene which is unsubstituted or substituted by one or two methyl groups; W18 is an oxo or thioxo group or a group NR64; W19 is an oxy, thio, sulfinyl or sulfonyl group or a group NR61; and W20 is a hydrocarbon radical L4; or
(e) W17 is a direct bond; W18 is an oxo or thioxo group or a group NR64; W19 is a nitrogen atom; and W20 is a hydrocarbon radical L5; or
(f) W17 is a methine group which is unsubstituted or substituted by one or two methyl groups; W19 is an oxo or thioxo group or a group NR64; W19 is a nitrogen atom; and W20 is a hydrocarbon radical L6; and
(g) W17 is a cis-vinylene group which is unsubstituted or substituted by one or two methyl groups; W18 is an oxo or thioxo group or a group NR64; W19 is a nitrogen atom; and W20 is a hydrocarbon radical L7;
R59 is a hydrogen; a (C1-C3)alkyl; a group xe2x80x94CH2COOR65; or a group xe2x80x94CH2CONR66R67,
R60 is a hydrogen; a (C1-C3)alkyl; a cyano; a nitro; or a (C1-C3)alkylsulfonyl group;
R61 is a hydrogen or a (C1-C3)alkyl;
R62 and R63 are each independently a hydrogen or a (C1-C3)alkyl;
or R62 and R63, together with the nitrogen atom to which they are bonded, form a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine (or its S-oxide) and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
R64 is a hydrogen or a (C1-C3)alkyl;
R65 is a hydrogen or a (C1-C3)alkyl;
R66 and R67 are each independently a hydrogen; a (C1-C3)alkyl; a phenyl; or a benzyl;
L3 is an ethylene, a cis-vinylene, a trimethylene or a tetramethylene, said hydrocarbon radical L3 being unsubstituted or substituted by one or two methyl groups;
L4 is an ethylene or a trimethylene, said hydrocarbon radical L4 being unsubstituted or substituted by one or two methyl groups;
L5 is a prop-2-en-1-yliden-3-yl which is unsubstituted or substituted by one or two methyl groups;
L6 is a cis-vinylene which is unsubstituted or substituted by one or two methyl groups; and
L7 is a methine which is unsubstituted or substituted by a (C1-C3)alkyl;
ixxe2x80x94or a group B9 of the formula 
in which J5 is:
a group 
in which:
X2 is a (C1-C6)alkyl; a group xe2x80x94CH2xe2x80x94OR68; a group xe2x80x94CH2xe2x80x94SR68; a group xe2x80x94CH2xe2x80x94S(O)R69; a group xe2x80x94CH2xe2x80x94SO2R69; a group xe2x80x94COOR68; a group xe2x80x94C(xe2x95x90W24)NR70R71; a group xe2x80x94C(R68)(OR72)(OR73); a group xe2x80x94CH2NR68C(xe2x95x90W24)R74; a group xe2x80x94CH2xe2x80x94NR68COOR74; or a group xe2x80x94CH2NR68C(xe2x95x90W24)NR70R71;
W21 is a direct bond and W22 is a hydrocarbon radical of which the 1-position is joined to W21, the hydrocarbon radical W22 being selected from a trimethylene, a tetramethylene, a cis-1-butenylene and a cis,cis-butadienylene;
or W21 is a group NR75 and W22 is a hydrocarbon radical selected from an ethylene, a trimethylene and a cis-vinylene;
or W21 is a nitrogen atom and W22 is a cis,cis-prop-2-en-1-yliden-3-yl radical of which the 1-position is joined to W21;
W23 is an oxygen atom or a sulfur atom;
W24 is an oxygen atom or a sulfur atom;
R68 is a hydrogen or a (C1-C6)alkyl;
R69 is a (C1-C6)alkyl;
R70 and R71, are each independently a hydrogen; a (C1-C6)alkyl which is unsubstituted or substituted by a hydroxyl or a (C1-C3)alkoxy; an xcfx89xe2x80x94HOxe2x80x94(C1-C6)alkyl; an xcfx89-(C1-C3)alkoxy-(C1-C6)alkyl; an xcfx89phenyl-(C1-C6)alkyl; an xcfx89xe2x80x94R76OOCxe2x80x94(C1-C6)alkyl; or an xcfx89xe2x80x94R77R78NCOxe2x80x94(C1-C6)alkyl;
or R70 and R71, together with the nitrogen atom to which they are bonded, form a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine (or its S-oxide) and piperazine which is unsubstituted or substituted in the 4-position by a methyl group or an ethyl group;
R72 and R73 are each independently a (C1-C3)alkyl;
or R72 and R73 together form a divalent hydrocarbon radical selected from an ethylene and a trimethylene;
R74 is a hydrogen or a (C1-C6)alkyl;
R75 is a hydrogen or a (C1-C6)alkyl;
R76 is a hydrogen or a (C1-C3)alkyl; and
R77 and R78 are each independently a hydrogen or a (C1-C3)alkyl;
xxe2x80x94or a group B10 of the formula 
in which J6 is:
a group 
in which:
X1 is as defined above for the group B1, X1 being other than hydrogen when W25 is a (C1-C7)alkyl or a (C3-C7)cycloalkyl;
W25 is a (C1-C7)alkyl or a (C3-C7)cycloalkyl; W25 can also be a group xe2x80x94NR79R80 when X1 is a hydrogen, a cyano, a carboxyl, a (C1-C7)alkoxycarbonyl or a group xe2x80x94CONR19R20; and
R79 and R80 are each independently a (C1-C7)alkyl;
or R79 and R80, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine and perhydroazepine,
with the proviso that:
1/when simultaneously:
R2 is a methyl group or R1 and R2 together form a group xe2x80x94(CH2)3xe2x80x94;
Ar1 is a 3,4-dichlorophenyl;
T is a group xe2x80x94CH2xe2x80x94; a group xe2x80x94COxe2x80x94; a group xe2x80x94COOxe2x80x94; or a group xe2x80x94CONR3;
A is a direct bond; a group xe2x80x94(CH2)txe2x80x94 in which t is one, two or three; or a vinylene group;
or xe2x80x94Txe2x80x94Axe2x80x94 is the group xe2x80x94SO2xe2x80x94; and
Z is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a halogen, a (C1-C4)alkyl, a (C1-C4)alkoxy or a nitro,
B is a group B1 of the formula 
in which J1 is a group 
in which:
x is zero;
Ar2 is a pyrid-2-yl or a phenyl which is unsubstituted or substituted by a halogen, a methyl or a (C1-C4)alkoxy; and
X1 is other than a group selected from:
formyl;
(C1-C6)alkylcarbonyl;
xe2x80x94(CH2)mxe2x80x94OR4 in which m is zero or one and R4 is a hydrogen or a (C1-C7)alkyl;
xe2x80x94(CH2)mxe2x80x94OCOR5 in which m is zero or one and R5 is a hydrogen or a (C1-C6)alkyl;
xe2x80x94(CH2)mxe2x80x94OCONH(C1-C7)alkyl in which m is one;
xe2x80x94NR8R9 in which R8 and R9 are each independently a hydrogen or a (C1-C7)alkyl;
R9 can also be a (C3-C7)cycloalkylmethyl, a benzyl or a phenyl; or R8 and R9, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine and perhydroazepine;
xe2x80x94(CH2)pxe2x80x94NR10R11 in which p is one and R10 and R11 are each independently a hydrogen or a (C1-C7)alkyl; R11 can also be a (C3-C7)cycloalkylmethyl or a benzyl;
xe2x80x94NR12COR13 in which R12 is a hydrogen or a (C1-C4)alkyl and R13 is a hydrogen, a (C1-C7)alkyl, a phenyl, a benzyl, a pyridyl or a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; or R12 and R13 together are a group xe2x80x94(CH2)uxe2x80x94 in which u is three or four;
xe2x80x94(CH2)pxe2x80x94NR14C(xe2x95x90W1)R16 in which p is one, W1 is an oxygen atom, R14 is a hydrogen or a (C1-C4)alkyl and R16 is a hydrogen, a (C1-C7)alkyl, a phenyl, a benzyl, a pyridyl or a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls;
xe2x80x94(CH2)mxe2x80x94NR14COOR17 in which m is zero or one, R14 is a hydrogen or a (C1-C4)alkyl and R17 is a (C1-C7)alkyl or a phenyl;
xe2x80x94(CH2)mxe2x80x94NR14SO2R18 in which m is zero or one, R14 is a hydrogen or a (C1-C4)alkyl and R18 is a (C1-C7)alkyl, an amino which is free or substituted by one or two (C1-C7)alkyls, or a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a (C1-C7)alkyl, a trifluoromethyl, a hydroxyl, a (C1-C7)alkoxy, a carboxyl, a (C1-C7)alkoxycarbonyl, a (C1-C7)alkylcarbonyloxy, a cyano, a nitro and an amino which is free or substituted by one or two (C1-C7)alkyls, said substituents being identical or different;
xe2x80x94(CH2)mxe2x80x94NR14C(xe2x95x90W1)NR19R20 in which m is zero or one, W1 is an oxygen atom, R14 is a hydrogen or a (C1-C4)alkyl and R19 and R20 are each independently a hydrogen or a (C1-C7)alkyl; R20 can also be a (C3-C7)cycloalkyl, a (C3-C7)cycloalkylmethyl, a hydroxyl, a (C1-C4)alkoxy, a benzyl or a phenyl; or R19 and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine and perhydroazepine;
xe2x80x94(CH2)nxe2x80x94COOR2, in which n is zero and R21 is a (C1-C7)alkyl;
xe2x80x94(CH2)nxe2x80x94C(xe2x95x90W1)NR19R20 in which n is zero, W1 is an oxygen atom and R19 and R20 are as defined above; and xe2x80x94CN;
or X1 does not form a double bond between the carbon atom to which it is bonded and the adjacent carbon atom of the piperidine ring;
or Ar2 and X1, together with the carbon atom to which they are bonded, are other than a group of the formula 
2/when R1 is hydrogen, R2 is the methyl group, Ar1 is other than 3,4-dichlorophenyl group and Txe2x80x94Axe2x80x94Z is the thenoyl group, B is the group B 1 in which J1 is the group 
in which x is one, Ar2 is the phenyl group and X1 is other than hydrogen;
3/when R1 is hydrogen, R2 is the methyl group, Ar1 is the 3,4-dichlorophenyl group and Txe2x80x94Axe2x80x94Z is the 2,4-dichlorobenzoyl group, B is the group B1 in which J1 is the group 
in which x is one, Ar2 is the phenyl group and X1 is other than hydrogen; or
4/when R1 and R2 together form a group xe2x80x94(CH2)3xe2x80x94, Ar1 is the 3,4-dichlorophenyl group and Txe2x80x94Axe2x80x94Z is the 2-(3-methoxyphenyl)acetyl group, B is the group B1 in which J1 is the group 
in which x is one, Ar2 is phenyl and X1 is other than hydrogen; and their salts, where appropriate, with mineral or organic acids.
The compounds of formula (I) according to the invention include the optically pure isomers as well as the racemates.
It is possible to form salts of the compounds of formula (I). These salts include those with mineral or organic acids which permit a suitable separation or crystallization of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, for example a mandelic or camphosulfonic acid, as well as those with mineral or organic acids which form pharmaceutically acceptable salts such as the hydrochloride, hydrobromide, sulfate, hydrogensulfate, dihydrogenphosphate, methanesulfonate, methylsulfate, maleate, fumarate, naphthalene-2-sulfonate, glycolate, gluconate, citrate, isethionate, benzenesulfonate and paratoluenesulfonate.
More particularly, the radical Z can be a phenyl group, which can be unsubstituted or may contain one or more substituents.
When Z is a phenyl group, it can be monosubstituted or disubstituted, especially in the 2,4-position but also, for example, in the 2,3-, 4,5-, 3,4- or 3,5-position; it can also be trisubstituted, especially in the 2,4,6-position but also, for example, in the 2,3,4-, 2,3,5-, 2,4,5- or 3,4,5-position, tetrasubstituted, for example in the 2,3,4,5-position, or pentasubstituted.
The radical Z can also be a bicyclic aromatic group such as 1- or 2-naphthyl or 1-, 2-, 3-, 4-, 5-, 6- or 7-indenyl, in which one or more bonds can be hydrogenated, it being possible for said groups to be unsubstituted or optionally to contain one or more substituents such as alkyl, phenyl, cyano, hydroxyalkyl, hydroxyl, oxo, alkylcarbonylamino, alkoxycarbonyl, thioalkyl, halogen, alkoxy and trifluoromethyl groups, in which the alkyls are C1-C4.
The radical Z can also be a group Zxe2x80xa2 selected from pyridyl, thiadiazolyl, indolyl, indazolyl, imidazolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzisothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzodioxinyl, isoxazolyl, benzopyranyl, thiazolyl, thienyl, furyl, pyranyl, chromenyl, isobenzofuranyl, pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, phthalazinyl, quinazolinyl, acridinyl, isothiazolyl, isochromanyl and chromanyl, in which one or more double bonds can be hydrogenated, it being possible for said groups to be unsubstituted or optionally to contain one or more substituents such as alkyl, phenyl, cyano, hydroxyalkyl, hydroxyl, alkylcarbonylamino, alkoxycarbonyl and thioalkyl groups, in which the alkyl and alkoxy groups are C1-C4.
In the present description the alkyl or alkoxy groups are linear or branched; halogen atom is understood as meaning a chlorine, bromine, fluorine or iodine atom.
In the present description, when B is a group B4 or B5, aryl is understood as meaning a phenyl radical or a C9-C10 ortho-fused bicyclic carbocyclic radical in which at least one of the rings is aromatic; heteroaryl is understood as meaning either a five- or six-membered monocyclic aromatic heterocycle containing from one to four heteroatoms, said heteroatoms being selected from an oxygen atom, a sulfur atom and a nitrogen atom, and said heterocycle being bonded by a carbon atom of the ring, or an eight- to ten-membered ortho-fused bicyclic aromatic heterocycle containing from one to four heteroatoms as defined above.
In the substituents of the group Z=phenyl, (C1-C10)alkyl is understood as meaning for example a methyl, an ethyl, an n-propyl, an isopropyl, an n-butyl, an isobutyl, a sec-butyl, a tert-butyl, a pentyl or n-pentyl, a hexyl or n-hexyl, a heptyl or n-heptyl, an octyl or n-octyl, a nonyl or n-nonyl or a decyl or n-decyl; (C3-C8)-cycloalkyl optionally substituted by a methyl is understood as meaning for example a cyclopropyl, a cyclobutyl, a cyclopentyl, a 1-, 2- or 3-methylcyclopentyl, a cyclohexyl, a 1-, 2-, 3- or 4-methylcyclohexyl, a cycloheptyl or a cyclooctyl; (C1-C10)alkoxy is understood as meaning for example a methoxy, an ethoxy, an n-propoxy, an isopropoxy, an n-butoxy, an isobutoxy, a sec-butoxy, a tert-butoxy, a pentoxy, a hexyloxy, a heptyloxy, an octyloxy, a nonyloxy or a decyloxy; (C3-C8)cycloalkoxy optionally substituted by a methyl is understood as meaning for example a cyclopropoxy, a cyclobutoxy, a cyclopentoxy, a 1-, 2- or 3-methylcyclopentoxy, a cyclohexyloxy, a 1-, 2-, 3- or 4-methylcyclohexyloxy, a cycloheptyloxy or a cyclooctyloxy; (C1-C10)alkylthio is understood as meaning for example a methylthio, an ethylthio, an n-propylthio, an isopropylthio, an n-butylthio, an isobutylthio, a sec-butylthio, a tert-butylthio, a pentylthio, a hexylthio, a heptylthio, an octylthio, a nonylthio or a decylthio; (C1-C6)alkylcarbonyloxy is understood as meaning for example an acetoxy, a propionyloxy, a butyryloxy, a valeryloxy, a caproyloxy or a heptanoyloxy; (C1-C6)alkylcarbonylamino is understood as meaning for example an acetylamino, a propionylamino, a butyrylamino, an isobutyrylamino, a valerylamino, a caproylamino or an heptanoylamino; (C1-C4)alkoxycarbonyl is understood as meaning for example a methoxycarbonyl, an ethoxycarbonyl, an n-propoxycarbonyl, an isopropoxycarbonyl, an n-butoxycarbonyl, an isobutoxycarbonyl, a sec-butoxycarbonyl or a tert-butoxycarbonyl; and (C3-C7)cycloalkoxycarbonyl is understood as meaning for example a cyclopropoxycarbonyl, a cyclobutoxycarbonyl, a cyclopentoxycarbonyl, a cyclohexyloxycarbonyl or a cycloheptyloxycarbonyl.
The invention relates particularly to compounds of formula (I) in which:
Z is Zxe2x80xa2 as defined above;
R1 and R2 together form a group xe2x80x94(CH2)3xe2x80x94;
Ar1 is a 3,4-dichlorophenyl;
T is a group xe2x80x94COxe2x80x94;
A is a direct bond; and
B is as defined for a compound of formula (I), and their salts, where appropriate, with mineral or organic acids.
Among these compounds, those of the formula 
in which:
Zxe2x80xa2 is as defined above; and
Bxe2x80xa2 is a group of the formula 
xe2x80x83in which Jxe2x80xa2 is:
ixe2x80xa2xe2x80x94either a group of the structure 
in which:
Wxe2x80xa2 is a phenyl or a benzyl and R19 and R20 are as defined for a compound of formula (J);
or Wxe2x80xa2 is a group xe2x80x94NR79R80 in which R79 and R80 are as defined for (I) and Rk19 and R20 are each hydrogen;
ixe2x80xa2xe2x80xa2xe2x80x94or a group of the structure 
in which:
Rxe2x80xa2 is hydrogen, a methyl group, an acetyl group, a methoxycarbonyl group, a dimethylaminocarbonyl group or a methanesulfonyl group,
and their salts, especially pharmaceutically acceptable salts, are advantageous.
Among these compounds, those of the formula 
in which:
Bxe2x80xa2 is as defied for a compound of formula (Ixe2x80xa2); and
Zxe2x80xa2xe2x80xa2 is a pyridyl, for example a 4-pyridyl, a 2-thienyl, a 3-thienyl, a 2-furyl or a 3-furyl,
and their salts, especially pharmaceutically acceptable salts, are particularly advantageous.
Among, these compounds, those of the formula 
in which:
Zxe2x80xa2xe2x80xa2 is as defined for a compound of formula (Ixe2x80xa2xe2x80xa2), and their salts, especially pharmaceutically acceptable salts, are of very great interest.
Advantageously the radical Z is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a halogen atom, more particularly a chlorine, fluorine or iodine atom, a trifluoromethyl, a (C1-C4)alkyl, a hydroxyl or a (C1-C4)alkoxy; a naphthyl which is unsubstituted or monosubstituted or polysubstituted by a halogen, a trifluoromethyl, a (C1-C4)alkyl, a hydroxyl or a (C1-C4)alkoxy; a pyridyl; a thienyl; an indolyl; a quinolyl; a benzothienyl; or an imidazolyl.
The invention relates particularly to compounds of formula (I) in which:
Z is Zxe2x80x2 and is:
a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom; a trifluoromethyl; a cyano; a hydroxyl; a nitro; an amino which is unsubstituted or monosubstituted or disubstituted by a (C1-C4)alkyl; a benzylamino; a carboxyl; a (C1-C10)alkyl; a (C3-C8)cycloalkyl which is unsubstituted or monosubstituted or polysubstituted by a methyl; a (C1-C10)alkoxy; a (C3-C8)cycloalkoxy which is unsubstituted or monosubstituted or polysubstituted by a methyl; a mercapto; a (C1-C10)alkylthio; a formyloxy; a (C1-C6)alkylcarbonyloxy; a formylamino; a (C1-C6)alkylcarbonylamino; a benzoyl-amino; a (C1-C4)alkoxycarbonyl; a (C3-C7)cycloalkoxycarbonyl; a carbamoyl which is unsubstituted or monosubstituted or disubstituted by a (C1-C4)alkyl; a ureido which is unsubstituted or monosubstituted or disubstituted in the 3-position by a (C1-C4)alkyl or a (C3-C7)cycloalkyl; and a (pyrrolidin-1-yl)-carbonylamino, said substituents being identical or different;
a naphthyl which is unsubstituted or monosubstituted or polysubstituted by a halogen, a trifluoromethyl, a (C1-C4)alkyl, a hydroxyl or a (C1-C4)alkoxy; or
a pyridyl; a thienyl; an indolyl; a quinolyl; a benzothienyl; or an imidazolyl, and their salts with mineral or organic acids.
The substituent Ar1 is preferably a phenyl group which is advantageously substituted by two chlorine atoms, more particularly in the 3- and 4-positions.
According to the present invention, the preferred compounds are those in which simultaneously:
Z is Zxe2x80x2;
Ar1 is a 3,4-dichlorophenyl;
R1 and R2 together form a group xe2x80x94(CH2)3 or xe2x80x94(CH2)4xe2x80x94; and
B, T and A are as defined for a compound of formula (I), and their salts, especially pharmaceutically acceptable salts.
When B is a group B3, W3 is advantageously an oxygen or sulfur atom, R28 is hydrogen, a (C1-C6)alkyl, a (C3-C7)cycloalkyl, preferably cyclohexyl, or a (C3-C4)alk-2-en-1-yl, preferably allyl, and R29 is hydrogen, a (C1-C6)alkyl, a trifluoromethyl or a (C1-C4)alkylamino, preferably methylamino, or, only when R28 is other than hydrogen, R29 is a di(C1-C5)alkylamino, preferably dimethylamino, or R28 and R29 together are a 1,3-propylene, 1,4-butylene or cis,cis-1,4-butadienylene group. Consequently the compounds of formula (I) in which B is B3 and W3, R28 and R29 are as just defined, and their salts, especially pharmaceutically acceptable salts, are advantageous products.
The compounds of this subclass of formula (I) in which simultaneously:
B is a group B3 in which:
either W3 is oxygen, R29 is a (C1-C4)alkyl or a trifluoromethyl and R28 is a (C1-C6)alkyl, especially an ethyl;
or W3 is oxygen, R28 is an allyl or a cyclohexyl and R29 is a methyl;
or W3 is oxygen, R28 is an ethyl and R29 is a methylamino or a dimethylamino;
or W3 is oxygen and R28 and R29 together form a 1,3-propylene, 1,4-butylene or cis,cis-1,4-butadienyl group;
or W3 is sulfur and R28 and R29 together form a 1,4-butylene group;
R1 and R2 together form a group xe2x80x94(CH2)3xe2x80x94 or xe2x80x94(CH2)4xe2x80x94;
Ar1 is a 3,4-dichlorophenyl;
Zxe2x95x90Zxe2x80x2; and
T and A are as defined above for a compound of formula (I), and their salts, especially pharmaceutically acceptable salts, are particularly preferred.
When B is a group B4, W4 is advantageously a (C1-C8)alkyl group substituted by a hydroxyl, oxo, hydroxyimino, (C1-C4)alkoxyimino, (C1-C4)alkanoyloxy, (C1-C4)alkanoylamino or (C1-C4)alkoxy group or at the same time by an oxo group and a hydroxyl or (C1-C4)alkoxy group or a group xe2x80x94NR33R34. Consequently the compounds of formula (I) in which B is a group B4 and W4 is an alkyl group substituted by a hydroxyl, oxo, hydroxyimino, (C1-C4)alkoxyimino, (C1-C4)alkanoyloxy, (C1-C4)alkanoylamino or (C1-C4)alkoxy group or at the same time by an oxo group and a hydroxyl or (C1-C4)alkoxy group or a group xe2x80x94NR33R34, and their salts, especially pharmaceutically acceptable salts, are advantageous products.
The compounds of this subclass of formula (I) in which simultaneously:
B is B4 in which: W4 is 1-hydroxypropyl, 1-hydroxyethyl, 1-hydroxybutyl, 2-hydroxybut-2-yl, 4-hydroxyhept-4-yl, 2-hydroxyethyl, 1-hydroxyiminopropyl (syn or anti), 1-methoxyiminopropyl (syn or anti), 2-acetoxyethyl, 2-acetamidoethyl, carboxyl, ethoxycarbonyl or pyrrolidin-1-ylcarbonyl;
R1 and R2 together form a group xe2x80x94(CH2)3xe2x80x94 or xe2x80x94(CH2)4xe2x80x94;
Ar1 is a 3,4-dichlorophenyl;
Zxe2x95x90Zxe2x80x2; and
T and A are as defined above for a compound of formula (I),
and their salts, especially pharmaceutically acceptable salts, are particularly preferred.
When B is a group B5, W6 is advantageously a hydrogen, W7 is a hydroxyl and W8 is a phenyl which is unsubstituted or substituted by a methoxy, a hydroxyl, a methylthio or a methylsulfinyl; or W6 and W7 are hydrogen and W8 is a pyridyl, pyrimidyl or thienyl group substituted by a halogen, especially chlorine or fluorine, or by one of the following groups: cyano, trifluoromethyl, hydroxyl, (C1-C5)alkoxy, especially methoxy or ethoxy, formyloxy, (C1-C4)alkylcarbonyloxy, especially acetoxy, amino, methylamino, dimethylamino, acetamido, imidazolin-2-yl, carboxyl, methoxycarbonyl, benzyloxycarbonyl, ethoxycarbonyl, carbamoyl, N,N-dimethylcarbamoyl, pyrrolidinocarbonyl, N-methylcarbamoyl, methylthio, methylsulfinyl, methylsulfonyl, (C1-C4)alkyl, especially methyl, ethyl, propyl, butyl, isopropyl, 2-methylpropyl or tert-butyl, formyl or (C1-C4)alkylcarbonyl, especially acetyl or propionyl; an indenyl, naphthyl, furyl, pyrrolyl, 1,3,4-oxadiazol-2-yl or benz[d]isoxazol-3-yl group which is unsubstituted or substituted by one of the substituents mentioned above for the pyridyl, pyrimidyl or thienyl groups; an imidazol-2-yl substituted by one of the substituents mentioned above for the pyridyl, pyrimidyl or thienyl groups, except for a (C1-C4)alkyl; or a phenyl group substituted by one of the substituents mentioned above for the pyridyl, pyrimidyl or thienyl groups, except for halogens and hydroxyl, trifluoromethyl, (C1-C4)alkyl and (C1-C4)alkoxy groups; or W7 is hydrogen and W6 and W8, together with a diradical W9 and the piperidine carbon atom to which they are bonded, form a spiro ring in which W8 is a phenyl substituted in the ortho position by the diradical W9, which is itself joined to W6, said phenyl being unsubstituted or substituted by a methoxy, a hydroxyl, a methylthio or a methylsulfinyl; the diradical W9 is a methylene or a carbonyl; and W6 is an oxy group. Consequently the compounds of formula (I) in which B is B5 and W6, W7 and W8 are as just defined, and their salts, especially pharmaceutically acceptable salts, are advantageous products.
The compounds of this subclass of formula (I) in which simultaneously:
B is a group B5 in which: W7 is a hydroxyl, W6 is a hydrogen and W8 is a phenyl; or W6 and W7 are hydrogen and W8 is selected from the following groups; 5-methyl- 1,3,4-oxadiazol-2-yl, 4-ethoxycarbonylimidazol-2-yl, 2-fluoropyrid-3-yl, 2-methylthiophenyl, 4-methylthiophenyl, 2-methylsulfinylphenyl, 4-methylsulfinylphenyl and 4-(N-methylcarbamoyl)phenyl; or W7 is hydrogen and W6 and W8, together with the piperidine to which they are bonded, form a spiro[isobenzofuran-1(3H),4xe2x80x2-piperid]-1xe2x80x2-yl group or a 3-oxospiro[isobenzofuran-1(3H),4xe2x80x2-piperid]-1xe2x80x2-yl group;
R1 and R2 together form a group xe2x80x94(CH2)3xe2x80x94 or xe2x80x94(CH2)4xe2x80x94;
Ar1 is a 3,4-dichlorophenyl;
Zxe2x95x90Zxe2x80x2; and
T and A are as defined above for a compound of formula (I),
and their salts, especially pharmaceutically acceptable salts, are particularly preferred.
Another group of preferred compounds of the invention consists of the compounds of formula (I) in which R1, R2, Ar1, T, A and Z are as defined above for (J) and B is the group B6.
The particularly preferred compounds of formula (I) are those in which simultaneously:
B is a group B6;
R1 and R2 together form a group xe2x80x94(CH2)3xe2x80x94 or xe2x80x94(CH2)4xe2x80x94;
Ar1 is a 3,4-dichlorophenyl;
Zxe2x95x90Zxe2x80x2; and
T and A are as defined above for a compound of formula (I),
and their salts, especially pharmaceutically acceptable salts.
When B is a group B7, f is advantageously one and g is two, or f is one and g is one and W12, W13, W14, W15 and W16, together with the carbon atom to which they are bonded, form one of the structures 1 to 201 described below, optionally substituted by a halogen, a (C1-C7)alkyl or a (C1-C7)alkoxy: 
Consequently the compounds of formula (1) in which B is B7 and g, f, W12, W13, W14, W15 and W16 are as just defined, and their salts, especially pharmaceutically acceptable salts, are advantageous products.
The compounds of this subclass of formula (I) in which simultaneously:
B is a group B7 selected from:
a) a 1-methanesulfonylspiro(indoline-3,4xe2x80x2-piperid-1xe2x80x2-yl)
b) a 1-benzyloxycarbonylspiro(indoline-3,4xe2x80x2-piperid-1xe2x80x2-yl)
c) a spiro(indoline-3,4xe2x80x2-piperid-1xe2x80x2-yl)
d) a 1-acetylspiro(indoline-3,4xe2x80x2-piperid-1xe2x80x2-yl)
e) a 1-propionylspiro(indoline-3,4xe2x80x2-piperid-1xe2x80x2-yl)
f) a 1-formylspiro(indoline-3,4xe2x80x2-piperid-1xe2x80x2-yl)
g) a 1-tert-butylcarbonylspiro(indoline-3,4xe2x80x2-piperid-1xe2x80x2-yl)
h) a 1-methylaminocarbonylspiro(indoline-3,4xe2x80x2-piperid-1xe2x80x2-yl)
i) a 1-ethoxycarbonylspiro(indoline-3,4xe2x80x2-piperid-1xe2x80x2-yl)
j) a 1-ethanesulfonylspiro(indoline-3,4xe2x80x2-piperid-1xe2x80x2-yl)
k) a 1-isopropanesulfonylspiro(indoline-3,4xe2x80x2-piperid-1xe2x80x2-yl)
l) a 1xe2x80x2-methyl-1-methanesulfonylspiro(indoline-3,4xe2x80x2-piperidinio-1xe2x80x2) iodide
m) a 1-(2-aminoacetyl)spiro(indoline-3,4xe2x80x2-piperid-1xe2x80x2-yl)
n) a 1-methylspiro(indol-2-one-3,4xe2x80x2-piperid-1xe2x80x2-yl)
o) a 2-methylspiro(isoindol-1-one-3,4xe2x80x2-piperid-1xe2x80x2-yl)
p) a spiro(2-oxotetrahydroquinoline-4-4xe2x80x2-piperid-1xe2x80x2-yl)
q) a 1-methylspiro(2-oxotetrahydroquinoline-4,4xe2x80x2-piperid-1xe2x80x2-yl)
r) a spiro(2,3-dihydrobenzothiophene-3,4xe2x80x2-piperid-1xe2x80x2-yl)
s) a 5-fluorospiro(2,3-dihydrobenzofuran-3,4xe2x80x2-pipenid-1xe2x80x2-yl)
t) a spiro(2,3-dihydrobenzofuran-3,4xe2x80x2-piperid-1xe2x80x2-yl)
u) a spiro(2,3-dihydrobenzothiophene-3,4xe2x80x2-piperid-1xe2x80x2-yl)1-oxide
v) a spiro(2,3-dihydrobenzothiophene-3,4xe2x80x2-piperid-1xe2x80x2-yl)1,1-dioxide
w) a 5-fluoro-1-methanesulfonylspiro(indoline-3,4xe2x80x2-piperid-1-yl)
x) a 1-methanesulfonyl-5-methoxyspiro(indoline-3,4xe2x80x2-piperid-1xe2x80x2-yl)
y) a 1-methanesulfonyl-5-methylspiro(indoline-3,4xe2x80x2-piperid-1xe2x80x2-yl)
z) a 5-chloro-1-methanesulfonylspiro(indoline-3,4xe2x80x2-piperid-1xe2x80x2-yl)
aa) a 7-fluoro-1-methanesulfonylspiro(indoline-3,4xe2x80x2-piperid-1xe2x80x2-yl)
ab) a 1-acetyl-5-fluorospiro(indoline-3,4xe2x80x2-piperid-1xe2x80x2-yl)
ac) a 1-acetyl-5-chlorospiro(indoline-3,4xe2x80x2-piperid-1xe2x80x2-yl)
ad) a 1-acetyl-5-methylspiro(indoline-3,4xe2x80x2-piperid-1xe2x80x2-yl)
ae) a 1-acetyl-6-fluorospiro(indoline-3,4xe2x80x2-piperid-1xe2x80x2-yl)
af) a 1-acetyl-4-fluorospiro(indoline-3,4xe2x80x2-piperid-1xe2x80x2-yl)
ag) a 1-(N,N-dimethylcarbamoyl)spiro(indoline-3,4xe2x80x2-piperid-1xe2x80x2-yl);
R1 and R2 together form a group xe2x80x94(CH2)3xe2x80x94 or xe2x80x94(CH2)4xe2x80x94;
Ar1 is a 3,4-dichlorophenyl;
Zxe2x95x90Zxe2x80x2; and
T and A are as defined above for (I),
and their salts, especially pharmaceutically acceptable salts, are particularly preferred.
When B is a group B8, W17 is advantageously a direct bond or a methylene group, preferably a direct bond, W18 is an oxo, thioxo, imino, methylimino or ethylimino group, preferably an oxo or thioxo group, W19 is an oxy or thio group or a group NH, preferably an oxy group or a group NH, and W20 is an ethylene, cis-vinylene or trimethylene group. Consequently the compounds of formula (I) in which B is B8 and W17, W18, W19 and W20 are as just defined, and their salts, especially pharmaceutically acceptable salts, are advantageous products.
The compounds of this subclass of formula (I) in which simultaneously:
B is a group B8 in which: W17 is a direct bond, W18 is an oxo or thioxo group, W19 is an oxy group or a group NH and W20 is an ethylene or trimethylene group;
R1 and R2 together form a group xe2x80x94(CH2)3xe2x80x94 or xe2x80x94(CH2)4xe2x80x94;
Ar1 is a 3,4-dichlorophenyl;
Zxe2x95x90Zxe2x80x2;and
T and A are as defined above for (I),
and their salts, especially pharmaceutically acceptable salts, are particularly preferred.
Another group of preferred compounds of the invention consists of the compounds of formula (I) in which R1, R2, Ar1, T, A and Z are as defined above for (I) and B is the group B9.
The particularly preferred compounds of formula (I) are those in which simultaneously:
B is a group B9 in which: X2 is a group xe2x80x94COOR68 or a group xe2x80x94C(xe2x95x90W24)NR70R7, and W21, W22 and W23, together with the nitrogen atom, form a 2-oxopiperidino group or a 2-oxoperhydropyrimidin-1-yl group;
R1 and R2 together form a group xe2x80x94(CH2)3xe2x80x94 or xe2x80x94(CH2)4xe2x80x94;
Ar1 is a 3,4-dichlorophenyl;
Zxe2x95x90Zxe2x80x2; and
T and A are as defined above for (I),
and their salts, especially pharmaceutically acceptable salts.
Another group of preferred compounds of the invention consists of the compounds of formula (I) in which R1, R2, Ar1, T, A and Z are as defined above for (I) and B is the group B10.
The particularly preferred compounds of formula (I) are those in which simultaneously:
B is a group B10;
R1 and R2 together form a group xe2x80x94(CH2)3xe2x80x94 or xe2x80x94(CH2)4xe2x80x94;
Ar1 is a 3,4-dichlorophenyl;
Zxe2x95x90Zxe2x80x2; and
T and A are as defined above for (I),
and their salts, especially pharmaceutically acceptable salts.
The more particularly preferred compounds of formula (I) are those in which simultaneously:
B is a group B10 in which J6 is a group 
in which:
W25 is a piperid-1-yl and X1 is a hydrogen, or W25 is an azetidin-1-yl, a pyrrolidin-1-yl, a pirerid-1-yl, a morpholin-4-yl, a thiomorpholin-4-yl or a perhydroazepin-1-yl and X1 is a carbamoyl;
R1 and R2 together form a group xe2x80x94(CH2)3xe2x80x94;
Ar1 is a 3,4-dichlorophenyl;
Zxe2x95x90Zxe2x80x2;
T is a group xe2x80x94COxe2x80x94; and
A is a direct bond,
and their salts, especially pharmaceutically acceptable salts.
Another group of preferred compounds of the invention are those of the formula 
in which:
Arxe2x80x21 is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C1-C4)alkoxy, a (C1-C4)-alkyl, a trifluoromethyl and a methylenedioxy, said substituents being identical or different;
Axe2x80x2 is a direct bond or a group xe2x80x94CH2xe2x80x94;
Zxe2x80x2 is as defined above; and
Ba is a group B1a of the formula 
in which J1a is a group 
in which:
x is zero;
Ar2a is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C1-C4)alkoxy, a (C1-C4)alkyl, a trifluoromethyl and a methylenedioxy, said substituents being identical or different; and
X1a is a group selected from:
hydrogen;
(C1-C7)alkyl;
xe2x80x94(CH2)mxe2x80x94OR4 in which m is two and R4 is a hydrogen or a (C1-C7)alkyl;
xe2x80x94(CH2)mxe2x80x94OCOR5 in which:
m is two and R5 is a hydrogen; a (C1-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; or a pyridyl; or m is zero or one and R5 is a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; or a pyridyl;
xe2x80x94(CH2)mxe2x80x94OCONH(C1-C7)alkyl in which m is zero or two;
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94OR6 in which R6 is a hydrogen; a (C1-C7)alkyl; a formyl; or a (C1-C7)alkylcarbonyl;
xe2x80x94(CH2)nxe2x80x94SR7 in which n is zero or one and R7 is a hydrogen or a (C1-C7)alkyl;
xe2x80x94CH2xe2x80x94S(O)jxe2x80x94(C1-C7)alkyl in which j is one or two;
xe2x80x94NR8R9 in which R8 and R9, together with the nitrogen atom to which they are bonded, form a piperazine heterocycle which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
xe2x80x94(CH2)pxe2x80x94NR10R11 in which p is two and R10 and R11 are each independently a hydrogen or a (C1-C7)alkyl; R11 can also be a (C3-C7)cycloalkylmethyl or a benzyl;
xe2x80x94NR12COR13 in which R12 is a hydrogen or a (C1-C7)alkyl and R13 is a vinyl, a furyl, a thienyl, a pyrrolyl or an imidazolyl;
xe2x80x94NR14COCOR15 in which R14 is a hydrogen or a (C1-C7)alkyl and R15 is a (C1-C4)alkoxy;
xe2x80x94(CH2)pxe2x80x94NR14C(xe2x95x90W1)R16 in which p is two, W1 is an oxygen atom or a sulfur atom, R14 is a hydrogen or a (C1-C7)alkyl and R16 is a hydrogen; a (C1-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl; and p is one, W1 is a sulfur atom and R14 and R16 are as just defined, or W1 is an oxygen atom, R14 is as just defined and R16 is a vinyl, a furyl, a thienyl, a pyrrolyl or an imidazolyl;
xe2x80x94(CH2)mxe2x80x94NR14COOR17 in which m is two, R14 is a hydrogen or a (C1-C7)alkyl and R17 is a (C1-C7)alkyl or a phenyl;
xe2x80x94(CH2)mxe2x80x94NR14SO2R18 in which m is two, R14 is a hydrogen or a (C1-C7)alkyl and R18 is a (C1-C7)alkyl; an amino which is free or substituted by one or two (C1-C7)alkyls; or a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a (C1-C7)alkyl, a trifluoromethyl, a hydroxyl, a (C1-C7)alkoxy, a carboxyl, a (C1-C7)alkylcarbonyloxy, a cyano, a nitro and an amino which is free or substituted by one or two (C1-C7)alkyls, said substituents being identical or different;
xe2x80x94(CH2)mxe2x80x94NR14C(xe2x95x90W1)NR19R20 in which m is two, W1 is an oxygen atom or a sulfur atom, R14 is a hydrogen or a (C1-C7)alkyl and R19 and R20 are each independently a hydrogen or a (C1-C7)alkyl; R20 can also be a (C3-C7)cycloalkyl; a (C3-C7)cycloalkylmethyl; a hydroxyl; a (C1-C4)alkoxy; a benzyl; a phenyl; or a (C1-C7)alkyl substituted by a hydroxyl, a (C1-C3)alkoxy, a phenyl, a carboxyl, a (C1-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (C1-C7)alkyls; or R19 and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl; and m is zero or one, W1 is a sulfur atom and R14, R19 and R20 are as just defined, or W1 is an oxygen atom, R14 and R19 are each independently a hydrogen or a (C1-C7)alkyl and R20 is a (C1-C7)alkyl substituted by a hydroxyl, a (C1-C3)alkoxy, a phenyl, a carboxyl, a (C1-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (C1-C7)alkyls; or R19 and R20, together with the nitrogen atom to which they are bonded, form a piperazine heterocycle which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
xe2x80x94(CH2)nxe2x80x94COOR21 in which n is one and R21 is a hydrogen or a (C1-C7)alkyl; and n is zero and R21 is a hydrogen;
xe2x80x94(CH2)nxe2x80x94C(xe2x95x90W1)NR19R20 in which n is one, W1 is an oxygen atom or a sulfur atom and R19 and R20 are each independently a hydrogen or a (C1-C7)alkyl; R20 can also be a (C3-C7)cycloalkyl; a (C3-C7)cycloalkylmethyl; a hydroxyl; a (C1-C4)alkoxy; a benzyl; a phenyl; or a (C1-C7)alkyl substituted by a hydroxyl, a (C1-C3)alkoxy, a phenyl, a carboxyl, a (C1-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (C1-C7)alkyls; or R19 and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl; and n is zero, W1 is a sulfur atom and R19 and R20 are as just defined, or W1 is an oxygen atom, R19 is a hydrogen or a (C1-C7)alkyl and R20 is a (C1-C7)alkyl substituted by a hydroxyl, a (C1-C3)alkoxy, a phenyl, a carboxyl, a (C1-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (C1-C7)alkyls; or R19 and R20, together with the nitrogen atom to which they are bonded, form a piperazine heterocycle which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
xe2x80x94COxe2x80x94NR22NR23R24 in which R22 is a hydrogen or a (C1-C7)alkyl and R23 and R24 are each independently a hydrogen or a (C1-C7)alkyl; 
in which R25 is a hydrogen or a (C1-C7)alkyl and R26 and R27 are each independently a hydrogen or a (C1-C7)alkyl; R27 can also be a formyl or a (C1-C7)alkylcarbonyl; and 
and their salts, especially pharmaceutically acceptable salts.
Among these compounds, those of the formula 
in which:
Bxe2x80x2a is a group Bxe2x80x21a of the formula 
in which Jxe2x80x21a is a group 
in which:
x is zero;
Ar2a is as defined for a compound of formula (Ia); and
Xxe2x80x21a is a group selected from:
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94OR6 in which R6 is a hydrogen; a (C1-C7)alkyl; a formyl; or a (C1-C7)alkylcarbonyl;
xe2x80x94NR12COR13 in which R12 is a hydrogen or a (C1-C7)alkyl and R13 is a vinyl, a furyl, a thienyl, a pyrrolyl or an imidazolyl;
xe2x80x94NR14COCOR15 in which R14 is a hydrogen or a (C1-C7)alkyl and R15 is a (C1-C4)alkoxy;
xe2x80x94(CH2)pxe2x80x94NR14C(xe2x95x90W1)R16 in which p is one, W1 is an oxygen atom, R14 is a hydrogen or a (C1-C7)alkyl and R16 is a vinyl, a furyl, a thienyl, a pyrrolyl or an imidazolyl;
xe2x80x94(CH2)mxe2x80x94NR14C(xe2x95x90W1)NR19R20 in which m is zero, W1 is an oxygen atom, R14 is a hydrogen or a (C1-C7)alkyl, R19 is a hydrogen or a (C1-C7)alkyl and R20 is a (C1-C7)alkyl substituted by a hydroxyl, a (C1-C3)alkoxy, a phenyl, a carboxyl, a (C1-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (C1-C7)alkyls;
xe2x80x94COxe2x80x94NR22xe2x80x94NR23R24 in which R22 is a hydrogen or a (C1-C7)alkyl and R23 and R24 are each independently a hydrogen or a (C1-C7)alkyl; 
in which R25 is a hydrogen or a (C1-C7)alkyl and R26 and R27 are each independently a hydrogen or a (C1-C7)alkyl; R27 can also be a formyl or a (C1-C7)alkylcarbonyl; and 
and their salts, especially pharmaceutically acceptable salts, are particularly preferred.
Among these compounds, those of the formula 
in which:
Xxe2x80x31a is a group selected from:
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94OR6 in which R6 is a hydrogen; a (C1-C7)alkyl; a formyl; or a (C1-C7)alkylcarbonyl, preferably a hydrogen or an acetyl;
xe2x80x94NR12COR13 in which R12 is a hydrogen or a (C1-C7)alkyl, preferably a hydrogen, and R13 is a vinyl, a furyl, a thienyl, a pyrrolyl or an imidazolyl, preferably a furyl or a thienyl;
xe2x80x94NR14COCOR15 in which R14 is a hydrogen or a (C1-C7)alkyl, preferably a hydrogen, and R15 is a (C1-C4)alkoxy, preferably an ethoxy; and 
in which R25 is a hydrogen or a (C1-C7)alkyl, preferably a hydrogen, and R26 and R27 are each independently a hydrogen or a (C1-C7)alkyl; R27 can also be a formyl or a (C1-C7)alkylcarbonyl; R26 and R27 are preferably a hydrogen; and 
and their salts, especially pharmaceutically acceptable salts, are more particularly preferred.
Another group of preferred compounds of the invention are those of the formula 
in which:
Arxe2x80x21 is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C1-C4)alkoxy, a (C1-C4)-alkyl, a trifluoromethyl and a methylenedioxy, said substituents being identical or different;
Axe2x80x2 is a direct bond or a group xe2x80x94CH2xe2x80x94;
Zxe2x80x2 is as defined above; and
Bb is a group B1b of the formula 
in which J1b is a group 
in which:
x is one;
Ar2a is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C1-C4)alkoxy, a (C1-C4)alkyl, a trifluoromethyl and a methylenedioxy, said substituents being identical or different; and
X1b is a group selected from:
hydrogen;
(C1-C7)alkyl;
formyl;
(C1-C7)alkylcarbonyl;
xe2x80x94(CH2)mxe2x80x94OR4;
xe2x80x94(CH2)mxe2x80x94OCOR5;
xe2x80x94(CH2)mxe2x80x94OCONHxe2x80x94(C1-C7)alkyl;
xe2x80x94Oxe2x80x94CH2CH2xe2x80x94OR6;
xe2x80x94(CH2)nxe2x80x94SR7;
xe2x80x94CH2xe2x80x94S(O)jxe2x80x94(C1-C7)alkyl;
xe2x80x94NR8R9;
xe2x80x94(CH2)pxe2x80x94NR10R11;
xe2x80x94NR12COR13;
xe2x80x94NR14COCOR15;
xe2x80x94(CH2)pxe2x80x94NR14C(xe2x95x90W1)R16;
xe2x80x94(CH2)mxe2x80x94NR14COOR17;
xe2x80x94(CH2)mxe2x80x94NR14SO2R18;
xe2x80x94(CH2)mxe2x80x94NR14C(xe2x95x90W1)NR19R20;
xe2x80x94(CH2)nxe2x80x94COOR21;
xe2x80x94(CH2)nxe2x80x94C(xe2x95x90W1)NR19R20;
xe2x80x94COxe2x80x94NR22xe2x80x94NR23R24;
xe2x80x94CN; 
xe2x80x83or X1b forms a double bond between the carbon atom to which it is bonded and the adjacent carbon atom of the piperidine ring,
in which groups:
m is zero, one or two;
n is zero or one;
p is one or two;
j is one or two;
W1 is an oxygen atom or a sulfur atom;
R4 is a hydrogen or a (C1-C7)alkyl;
R5 is a hydrogen; a (C1-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; or a pyridyl;
R6 is a hydrogen; a (C1-C7)alkyl; a formyl; or a (C1-C7)alkylcarbonyl;
R7 is a hydrogen or a (C1-C7)alkyl;
R8 and R9 are each independently a hydrogen or a (C1-C7)alkyl; R9 can also be a (C3-C7)cycloalkylmethyl, a benzyl or a phenyl;
or R8 and R9, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
R10 and R11 are each independently a hydrogen or a (C1-C7)alkyl; R11 can also be a (C3-C7)cycloalkylmethyl or a benzyl;
R12 is a hydrogen or a (C1-C7)alkyl;
R13 is a hydrogen; a (C1-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl;
or R12 and R13 together are a group xe2x80x94(CH2)uxe2x80x94 in which u is three or four;
R14 is a hydrogen or a (C1-C7)alkyl;
R15 is a (C1-C4)alkoxy;
R16 is a hydrogen; a (C1-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl;
R17 is a (C1-C7)alkyl or a phenyl;
R18 is a (C1-C7)alkyl; an amino which is free or substituted by one or two (C1-C7)alkyls; or a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a (C1-C7)alkyl, a trifluoromethyl, a hydroxyl, a (C1-C7)alkoxy, a carboxyl, a (C1-C7)alkoxycarbonyl, a (C1-C7)alkylcarbonyloxy, a cyano, a nitro and an amino which is free or substituted by one or two (C1-C7)alkyls, said substituents being identical or different;
R19 and R20 are each independently a hydrogen or a (C1-C7)alkyl; R20 can also be a (C3-C7)cycloalkyl; a (C3-C7)cycloalkylmethyl; a hydroxyl; a (C1-C4)alkoxy; a benzyl; a phenyl; or a (C1-C7)alkyl substituted by a hydroxyl, a (C1-C3)alkoxy, a phenyl, a carboxyl, a (C1-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (C1-C7)alkyls;
or R19 and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
R21 is a hydrogen or a (C1-C7)alkyl;
R22 is a hydrogen or a (C1-C7)alkyl;
R23 and R24 are each independently a hydrogen or a (C1-C7)alkyl;
R25 is a hydrogen or a (C1-C7)alkyl; and
R26 and R27 are each independently a hydrogen or a (C1-C7)alkyl; R27 can also be a formyl or a (C1-C7)alkylcarbonyl,
with the proviso that:
when Arxe2x80x21 is the 3,4-dichlorophenyl group and xe2x80x94Axe2x80x2xe2x80x94Zxe2x80x2 is the 3-methoxybenzyl group, Bb is the group B1b of the formula 
in which x is one, Ar2a is a phenyl group and X1b is other than hydrogen, and their salts, especially pharmaceutically acceptable salts.
Among these compounds, those of the formula 
in which:
Bxe2x80x2b is a group Bxe2x80x21b of the formula 
in which:
x is one;
Ar2a is as defined for a compound of formula (Ib); and
Xxe2x80x21b is as group s elected from:
xe2x80x94(C1-C7)alkyl;
xe2x80x94(CH2)mxe2x80x94OR4 in which m is one or two and R4 is a hydrogen or a (C1-C7)alkyl;
xe2x80x94(CH2)mxe2x80x94OCOR5 in which:
m is zero and R5 is a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; or a pyridyl; or
m is one or two and R5 is a hydrogen; a (C1-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; or a pyridyl;
xe2x80x94(CH2)mxe2x80x94OCONHxe2x80x94(C1-C7)alkyl in which m is zero, one or two;
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94OR6 in which R6 is a hydrogen; a (C1-C7)alkyl; a formyl; or a (C1-C7)alkylcarbonyl;
xe2x80x94(CH2)nxe2x80x94SR7 in which n is zero or one and R7 is a hydrogen or a (C1-C7)alkyl;
xe2x80x94CH2xe2x80x94S(O)jxe2x80x94(C1-C7)alkyl in which j is one or two;
xe2x80x94NR8R9 in which R8 is a hydrogen or a (C1-C7)alkyl and R9 is a (C3-C7)cycloalkylmethyl or a benzyl; or R8 and R9, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
xe2x80x94(CH2)pxe2x80x94NR10R11 in which p is one or two and R10 and R11 are each independently a hydrogen or a (C1-C7)alkyl; R11 can also be a (C3-C7)cycloalkylmethyl or a benzyl;
xe2x80x94NR12COR13 in which R12 is a hydrogen or a (C1-C7)alkyl and R13 is a (C3-C7)-cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl; or R12 and R13 together are a group xe2x80x94(CH2)uxe2x80x94 in which u is three or four;
xe2x80x94NR14COCOR15 in which R14 is a hydrogen or a (C1-C7)alkyl and R15 is a (C1-C4)alkoxy;
xe2x80x94(CH2)pxe2x80x94NR14C(xe2x95x90W1)R16 in which p is one or two, W1 is an oxygen atom or a sulfur atom, R14 is a hydrogen or a (C1-C7)alkyl and R16 is a hydrogen; a (C1-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl;
xe2x80x94(CH2)mxe2x80x94NR14COOR17 in which m is zero, one or two, R14 is a hydrogen or a (C1-C7)alkyl and R17 is a (C1-C7)alkyl or a phenyl;
xe2x80x94(CH2)mxe2x80x94NR14SO2R18 in which m is zero, one or two, R14 is a hydrogen or a (C1-C7)alkyl and R18 is a (C1-C7)alkyl; an amino which is free or substituted by one or two (C1-C7)alkyls; or a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a (C1-C7)alkyl, a trifluoromethyl, a hydroxyl, a (C1-C7)alkoxy, a carboxyl, a (C1-C7)alkoxycarbonyl, a (C1-C7)alkylcarbonyloxy, a cyano, a nitro and an amino which is free or substituted by one or two (C1-C7)alkyls, said substituents being identical or different;
xe2x80x94(CH2)mxe2x80x94NR14C(xe2x95x90W1)NR19R20 in which m is zero, one or two, W1 is an oxygen atom or a sulfur atom, R14 is a hydrogen or a (C1-C7)alkyl and R19 and R20 are each independently a hydrogen or a (C1-C7)alkyl; R20 can also be a (C3-C7)-cycloalkyl; a (C3-C7)cycloalkylmethyl; a hydroxyl; a (C1-C4)alkoxy; a benzyl; a phenyl; or a (C1-C7)alkyl substituted by a hydroxyl, a (C1-C3)alkoxy, a phenyl, a carboxyl, a (C1-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (C1-C7)alkyls; or R19 and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
xe2x80x94(CH2)nxe2x80x94COOR21 in which n is one and R21 is a hydrogen or a (C1-C7)alkyl;
xe2x80x94(CH2)nxe2x80x94C(xe2x95x90W1)NR19R20 in which n is zero or one, W1 is an oxygen atom or a sulfur atom and R19 and R20 are each independently a hydrogen or a (C1-C7)-alkyl; R20 can also be a (C3-C7)cycloalkyl; a (C3-C7)cycloalkylmethyl; a hydroxyl; a (C1-C4)alkoxy; a benzyl; a phenyl; or a (C1-C7)alkyl substituted by a hydroxyl, a (C1-C3)alkoxy, a phenyl, a carboxyl, a (C1-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (C1-C7)alkyls; or R19 and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
xe2x80x94COxe2x80x94NR22xe2x80x94NR23R24 in which R22 is a hydrogen or a (C1-C7)alkyl and R23 and R24 are each independently a hydrogen or a (C1-C7)alkyl; 
in which R25 is a hydrogen or a (C1-C7)alkyl and R26 and R27 are each independently a hydrogen or a (C1-C7)alkyl; R27 can also be a formyl or a (C1-C7)alkylcarbonyl; and 
and their salts, especially pharmaceutically acceptable salts, are particularly preferred.
Among these compounds, those of the formula 
in which:
Xxe2x80x31b is a group selected from:
xe2x80x94(CH2)pxe2x80x94NR10R11 in which p is one and R10 and R11 are each a hydrogen;
xe2x80x94(CH2)pxe2x80x94NR14C(xe2x95x90W1)R16 in which p is one, W1 is an oxygen atom, R14 is a hydrogen or a (C1-C7)alkyl and R16 is a (C1-C7)alkyl, preferably an ethyl;
xe2x80x94(CH2)mxe2x80x94NR14COOR17 in which m is zero, R14 is a hydrogen and R17 is a (C1-C7)alkyl, preferably an ethyl; and
xe2x80x94(CH2)mxe2x80x94C(xe2x95x90W1)NR19R20 in which n is zero, W1 is an oxygen atom and R19 and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl, preferably pyrrolidine,
and their salts, especially pharmaceutically acceptable salts, are more particularly preferred.
Another group of preferred compounds of the invention are those of the formula 
in which:
Arxe2x80x21 is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C1-C4)alkoxy, a (C1-C4)-alkyl, a trifluoromethyl and a methylenedioxy, said substituents being identical or different;
Axe2x80x2 is a direct bond or a group xe2x80x94CH2xe2x80x94;
Zxe2x80x2 is as defined above; and
Bc is a group B1c of the formula 
in which J1c is a group 
in which:
x is zero or one;
Ar2a is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C1-C4)alkoxy, a (C1-C4)alkyl, a trifluoromethyl and a methylenedioxy, said substituents being identical or different; and
X1b is as defined above for a compound of formula (Ib),
and their salts, especially pharmaceutically acceptable salts.
Among these compounds, those of the formula 
in which:
Bxe2x80x2c is a group Bxe2x80x21c of the formula 
in which Jxe2x80x21c is a group 
in which:
x is zero or one;
Ar2a is as defined for a compound of formula (Ic); and
Xxe2x80x21b is a group selected from:
(C1-C7)alkyl;
xe2x80x94(CH2)mxe2x80x94OR4 in which m is one or two and R4 is a hydrogen or a (C1-C7)alkyl;
xe2x80x94(CH2)mxe2x80x94OCOR5 in which m is zero and R5 is a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; or a pyridyl; and m is one or two and R5 is a hydrogen; a (C1-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; or a pyridyl;
xe2x80x94(CH2)mxe2x80x94OCONHxe2x80x94(C1-C7)alkyl in which m is zero, one or two;
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94OR6 in which R6 is a hydrogen; a (C1-C7)alkyl; a formyl; or a (C1-C7)alkylcarbonyl;
xe2x80x94(CH2)mxe2x80x94SR7 in which n is zero or one and R7 is a hydrogen or a (C1-C7)alkyl;
xe2x80x94CH2xe2x80x94S(O)jxe2x80x94(C1-C7)alkyl in which j is one or two;
xe2x80x94NR8R9 in which R8 is a hydrogen or a (C1-C7)alkyl and R9 is a (C3-C7)cyclo-alkylmethyl or a benzyl; or R8 and R9, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
xe2x80x94(CH2)pxe2x80x94NR10R11 in which p is one or two, R10 is a hydrogen or a (C1-C7)alkyl and R11 is a hydrogen, a (C1-C7)alkyl, a (C3-C7)cycloalkylmethyl or a benzyl;
xe2x80x94NR12COR13 in which R12 is a hydrogen or a (C1-C7)alkyl and R13 is a (C3-C7)-cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl; or R12 and R13 together form a group xe2x80x94(CH2)u in which u is three or four;
xe2x80x94NR14COCOR15 in which R14 is a hydrogen or a (C1-C7)alkyl and R15 is a (C1-C4)alkoxy;
xe2x80x94(CH2)pxe2x80x94NR14C(xe2x95x90W1)R16 in which p is one or two, W1 is an oxygen atom or a sulfur atom, R14 is a hydrogen or a (C1-C7)alkyl and R16 is a hydrogen; a (C1-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl;
xe2x80x94(CH2)mxe2x80x94NR14COOR17 in which m is zero, one or two, R14 is a hydrogen or a (C1-C7)alkyl and R17 is a (C1-C7)alkyl or a phenyl;
xe2x80x94(CH2)mxe2x80x94NR14SO2R18 in which m is zero, one or two, R14 is a hydrogen or a (C1-C7)alkyl and R18 is a (C1-C7)alkyl; an amino which is free or substituted by one or two (C1-C7)alkyls; or a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a (C1-C7)alkyl, a trifluoromethyl, a hydroxyl, a (C1-C7)alkoxy, a carboxyl, a (C1-C7)alkoxycarbonyl, a (C1-C7)alkylcarbonyloxy, a cyano, a nitro and an amino which is free or substituted by one or two (C1-C7)alkyls, said substituents being identical or different;
xe2x80x94(CH2)mxe2x80x94NR14C(xe2x95x90W1)NR19R20 in which m is zero, one or two, W1 is an oxygen atom or a sulfur atom, R14 is a hydrogen or a (C1-C7)alkyl and R19 and R20 are each independently a hydrogen or a (C1-C7)alkyl; R20 can also be a (C3-C7)-cycloalkyl; a (C3-C7)cycloalkylmethyl; a hydroxyl; a (C1-C4)alkoxy; a benzyl; a phenyl; or a (C1-C7)alkyl substituted by a hydroxyl, a (C1-C3)alkoxy, a phenyl, a carboxyl, a (C1-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (C1-C7)alkyls; or R19 and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
xe2x80x94(CH2)nxe2x80x94COOR2, in which n is one and R21 is a hydrogen or a (C1-C7)alkyl;
xe2x80x94(CH2)nxe2x80x94C(xe2x95x90W1)NR19R20 in which n is zero or one, W1 is an oxygen atom or a sulfur atom and R19 and R20 are each independently a hydrogen or a (C1-C7)-alkyl; R20 can also be a (C3-C7)cycloalkyl; a (C3-C7)cycloalkylmethyl; a hydroxyl; a (C1-C4)alkoxy; a benzyl; a phenyl; or a (C1-C7)alkyl substituted by a hydroxyl, a (C1-C3)alkoxy, a phenyl, a carboxyl, a (C1-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (C1-C7)alkyls; or R19 and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
xe2x80x94COxe2x80x94NR22xe2x80x94NR23R24 in which R22 is a hydrogen or a (C1-C7)alkyl and R23 and R24 are each independently a hydrogen or a (C1-C7)alkyl; 
in which R25 is a hydrogen or a (C1-C7)alkyl and R26 and R27 are each independently a hydrogen or a (C1-C7)alkyl; R27 can also be a formyl or a (C1-C7)alkylcarbonyl; and 
and their salts, especially pharmaceutically acceptable salts, are particularly preferred.
The following compounds:
1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(pyrrolidin-1-ylcarbonyl)-piperid-1-yl]propyl]piperidine;
1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-(4-piperidinopiperid-1-yl)-propyl]piperidine;
1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-(4-carbamoyl-4-piperidinopiperid-1-yl)propyl]piperidine;
3-[3-[4-(acryloyl-N-methylamino)-4-phenylpiperid-1-yl]propyl-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;
3-[3-[4-(2-aminothiazol-4-yl)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;
3-[3-(4-acetyl-4-benzylpiperid-1-yl)propyl]-1-benzoyl-3-(3,4-dichloro-phenyl)piperidine;
3-[3-[4-(acetylamino)-4-benzylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;
1-benzoyl-3-[3-[4-benzyl-4-(propionylaminomethyl)piperid-1-yl]propyl]-3-(3,4-dichlorophenyl)piperidine;
1-benzoyl-3-[3-[4-benzyl-4-(ethoxycarbonylamino)piperid-1-yl]propyl]-3-(3,4-dichlorophenyl)piperidine;
1-benzoyl-3-[3-[4-benzyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]-3-(3,4-dichlorophenyl)piperidine;
1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(dimethylaminocarbonyl)-4-phenylpiperid-1-yl]propyl]perhydroazepine;
1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-hydroxyethoxy)-4-phenyl-piperid-1-yl]propyl]piperidine;
3-[3-[4-(2-acetoxyethoxy)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;
1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-furoylamino)-4-phenylpiperid-1-yl]propyl]piperidine;
1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-thenoylamino)-4-phenyl-piperid-1-yl]propyl]piperidine;
3-(3,4-dichlorophenyl)-1-isonicotinoyl-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidine;
1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-spiro(indoline-3,4xe2x80x2-piperid-1xe2x80x2-yl)propyl]piperidine;
1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-acetylspiro(indoline-3,4xe2x80x2-piperid-1-yl)]propyl]piperidine;
3-(3,4-dichlorophenyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]-1-(2-thenoyl)piperidine;
3-(3,4-dichlorophenyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]-1-(3-thenoyl)piperidine;
3-(3,4-dichlorophenyl)-1-(2-furoyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidine;
3-(3,4-dichlorophenyl)-1-(3-furoyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidine;
3-[3-[4-(2-amino-1,3,4-oxadiazol-5-yl)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;
1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(ethoxalylamino)-4-phenyl-piperid-1-yl]propyl]piperidine;
1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-(4-carbamoyl-4-morpholinopiperid-1-yl)propyl]piperidine;
1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-(methoxycarbonyl)spiro(indoline-3,4xe2x80x2-piperid-1xe2x80x2-yl)]propyl]piperidine;
1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-(N,N-dimethylcarbamoyl)spiro(indoline-3,4xe2x80x2-piperid-1xe2x80x2-yl)]propyl]piperidine; and
1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-(methanesulfonyl)spiro(indoline-3,4xe2x80x2-piperid-1xe2x80x2-yl)]propyl]piperidine, in the form of racemates or one of their (+) or (xe2x88x92) enantiomers,
and their salts, especially pharmaceutically acceptable salts, are very particularly preferred according to the present invention.
The invention further relates, where they exist, to the solvates of the compounds of the invention and their salts, namely the compounds of formulae (I), (Ixe2x80xa2), (Ixe2x80xa2xe2x80xa2), (Ixe2x80xa2xe2x80xa2a), (Ia), (Ixe2x80x2a), (Ixe2x80x3a), (Ib), (Ixe2x80x2b), (Ixe2x80x3b), (Ic) and (Ixe2x80x2c) and their salts.
The compounds according to the invention are obtained by known methods, particularly those described in patent applications EP-A-474 561 and EP-A-512 901.
One of the methods suitable for obtaining the compounds of formula (I) and their salts is described below.
According to this method:
1) a compound of the formula 
in which Ar1, R1 and R2 are as defined for a compound of formula (I) and E is hydrogen or an O-protecting group, is treated:
either with a halogenated derivative of the formula
Hal-CH2xe2x80x94Axe2x80x94Z xe2x80x83xe2x80x83(III) 
in which Hal is a halogen atom, preferably bromine, and A and Z are as defined for a compound of formula (I), when it is desired to prepare a compound of formula (I) in which T is a group xe2x80x94CH2xe2x80x94;
or with a functional derivative of an acid of the formula
HOxe2x80x94COxe2x80x94Axe2x80x94Z xe2x80x83xe2x80x83(IIIa) 
in which A and Z are as defined above, when it is desired to prepare a compound of formula (I) in which T is a group xe2x80x94COxe2x80x94;
or with a chloroformate of the formula
Clxe2x80x94COOxe2x80x94Axe2x80x94Z xe2x80x83xe2x80x83(IIIb) 
in which A and Z are as defined above, when it is desired to prepare a compound of formula (I) in which T is group xe2x80x94COOxe2x80x94;
or with an isocyanate of the formula
Oxe2x95x90Cxe2x95x90Nxe2x80x94Axe2x80x94Z xe2x80x83xe2x80x83(IIIc) 
in which A and Z are as defined above, when it is desired to prepare a compound of formula (I) in which T is a group xe2x80x94COxe2x80x94NR3xe2x80x94 in which R3 is hydrogen;
or with a carbamoyl chloride of the formula 
in which A and Z are as defined above and Rxe2x80x23 is a (C1-C4)alkyl, when it is desired to prepare a compound of formula (I) in which T is xe2x80x94CONR3xe2x80x94 in which R3 is a (C1-C4)alkyl;
or with a sulfonyl chloride of the formula
Clxe2x80x94SO2xe2x80x94Z xe2x80x83xe2x80x83(IIIe) 
in which Z is as defined above, when it is desired to prepare a compound of formula (I) in which xe2x80x94Txe2x80x94Axe2x80x94 is a group xe2x80x94SO2xe2x80x94, to give a compound of the formula 
2) the O-protecting group, if present, is removed from the compound of formula (IV), by reaction with an acid or a base, to give the alcohol of the formula 
xe2x80x833) the alcohol (V) is treated with a compound of the formula
Gxe2x80x94SO2xe2x80x94Cl xe2x80x83xe2x80x83(VI) 
in which G is a methyl, phenyl, tolyl or trifluoromethyl group, to give a compound of the formula 
xe2x80x834) the compound (VII) is reacted:
either with a cyclic secondary amine of the formula 
in which Jxe2x80x21 is:
* either a group 
in which Ar2 and x are as defined for (I) and Xxe2x80x21 is either X1 as defined for (I), or a precursor of X1, it being understood that when Xxe2x80x21 contains a hydroxyl group or an amino group, these groups can be protected;
* either a group 
in which Ar2 is as defined for (I);
* or a group 
in which Ar2 is as defined for (I);
* or a group 
in which Ar2 is as defined for (I);
* or a group 
in which Ar2, Am1 and r are as defined for (I);
or a group 
in which Ar2 and W2 are as defined for (I);
or with a cyclic secondary amine of the formula 
in which J2 is as defined above for (I);
or with a cyclic secondary amine of the formula 
in which J3 is as defined above for (I);
or with a cyclic secondary amine of the formula 
in which W4 is as defined above for (I);
or with a cyclic secondary amine of the formula 
in which W6, W7 and W8 are as defined above for (I);
or with a cyclic secondary amine of the formula 
in which J4 is as defined above for (I);
or with a compound of the formula 
in which f, g, W12, W13, W14, W15 and W16 are as defined above for (I);
or with a cyclic secondary amine of the formula 
in which W17, W18, W19 and W20 are as defined above for (I);
or with a cyclic secondary amine of the formula 
in which J5 is as defined above for (I);
or a cyclic secondary amine of the formula 
in which Jxe2x80x26 is a group 
in which W25 is as defined above for (I) and Xxe2x80x21 is X1 as defined for (I), or a precursor of X1, it being understood that when Xxe2x80x21 contains a hydroxyl group or an amino group, these groups can be protected; and
5) after deprotection of the hydroxyl groups or amino groups, if appropriate, or conversion of Xxe2x80x21 to X1, if appropriate, the resulting product is optionally converted to one of its salts with a mineral or organic acid.
In one variant of the method:
1xe2x80x2) the nitrogen atom of the compound of formula (II) is protected to give a compound of the formula 
in which Ar1, R1 and R2 are as defined for a compound of formula (I), E is hydrogen or an O-protecting group and Pr is an N-protecting group such as the trityl, tert-butoxycarbonyl or benzyloxycarbonyl group;
2xe2x80x2) the O-protecting group is eventually removed from the compound of formula (XVII), by reaction with an acid or a base, to give the alcohol of the formula 
3xe2x80x2) the alcohol (XVUI) is treated with a compound of formula (VI) as defined above to give a compound of the formula 
4xe2x80x2) the compound (XIX) is reacted with a compound of formula (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VIIIi) or (VIIIj) as defined above to give a compound of the formula 
in which B is as defined for a compound of formula (I), it being understood that when B contains a hydroxide group or an amino group, these groups can be protected;
5xe2x80x2) the protecting group Pr is selectively removed from the compound of formula (XX) to give the compound of the formula 
6xe2x80x2) the compound of formula (XXI) is treated with a compound of formula (III), (IIIa), (IIIb), (IIIc), (IIId) or (IIIe) as defined above; and
7xe2x80x2) after deprotection of the hydroxyl groups or amino groups, if appropriate, the resulting product is optionally converted to one of its salts with a mineral or organic acid.
More particularly, the compounds of formula (Ixe2x80xa2) and their salts, especially pharmaceutically acceptable salts, are prepared by the variant of the general method described above in which:
1xe2x80xa2) a compound of the formula 
in which G is a methyl, phenyl, tolyl or trifluoromethyl group and Pr is an N-protecting group such as the trityl, tert-butoxycarbonyl or benzyloxycarbonyl group, is reacted with a compound of the formula 
in which Jxe2x80xa2 is as defined for a compound of formula (Ixe2x80xa2), to give a compound of the formula 
2xe2x80xa2) the protecting group Pr is selectively removed from the compound of formula (XXxe2x80xa2) to give the compound of the formula 
xe2x80x833xe2x80xa2) the compound of formula (XXIxe2x80xa2) is treated with a functional derivative of an acid of the formula
HOxe2x80x94COxe2x80x94Zxe2x80xa2xe2x80x83xe2x80x83(III) 
in which Zxe2x80xa2 is as defined for a compound of formula (Ixe2x80xa2); and
4xe2x80xa2) after deprotection, if appropriate, the resulting product (Ixe2x80xa2) is optionally converted to one of its salts with a mineral or organic acid.
During any one of the steps for the preparation of the compounds of formula (I) or (Ixe2x80xa2), and more particularly when using compounds of formula (VIIIa), (VIIIb), (VIIIc), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VIIIi), (VIIIj) or (VIIIxe2x80xa2) or intermediates of formula (II), (IV), (XX), (XXI), (XXxe2x80xa2) or (XXIxe2x80xa2), it may be necessary and/or desirable to protect the reactive or sensitive functional groups, such as the amine, hydroxyl or carboxyl groups, present on any one of the molecules in question. This protection can be effected using the conventional protecting groups such as those described in Protective Groups in Organic Chemistry, J. F. W. McOmie, published by Plenum Press, 1973, and in Protective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wutts, published by John Wiley and Sons, 1991. The protecting groups can be removed in an appropriate subsequent step by using the methods known to those skilled in the art which do not affect the rest of the molecule in question.
Thus, when E is an O-protecting group, it is selected from the conventional O-protecting groups known to those skilled in the art, for example tetrahydropyran-2-yl, benzoyl and a (C1-C4)alkylcarbonyl.
The O-protecting groups which may be used to obtain a compound of formula (I) in which X1 contains a hydroxyl are the conventional O-protecting groups known to those skilled in the art, as defined above for E.
The N-protecting groups which may be used to obtain a compound of formula (I) in which X1 contains an amino group are the conventional N-protecting groups known to those skilled in the art, for example the trityl, methoxytrityl, tert-butoxycarbonyl or benzyloxycarbonyl group.
In step 1) of the method or in step 6xe2x80x2) of the variant, when using a halogenated derivative of formula (III), the reaction is carried out in an inert solvent such as tetrahydrofuran, N,N-dimethylformamide or dimethyl sulfoxide, in the presence of a base such as potassium tert-butylate, sodium hydride or lithium diisopropylamide, at a temperature between 0xc2x0 C. and 80xc2x0 C.
In step 1), in step 6xe2x80x2) or in step 3xe2x80xa2), the functional derivative of the acid (IIIa) or (IIIxe2x80xa2) used is the acid itself or one of the functional derivatives which react with amines, for example an anhydride, a mixed anhydride, the acid chloride or an activated ester such as the paranitrophenyl ester.
When using the acid of formula (IIIa) or (IIIxe2x80xa2) itself, the reaction is carried out in the presence of a coupling agent used in peptide chemistry, such as 1,3-dicyclohexylcarbodiimide or benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate, in the presence of a base such as triethylamine or N,N-diisopropylethylamine, in an inert solvent such as dichloromethane or N,N-dimethylformamide, at a temperature between 0xc2x0 C. and room temperature.
When using an acid chloride, the reaction is carried out in an inert solvent such as dichloromethane or benzene, in the presence of a base such as triethylamine or N-methylmorpholine, at a temperature between xe2x88x9260xc2x0 C. and room temperature.
When using a chloroformate of formula (IIIb), the reaction is carried out in an inert solvent such as dichloromethane, at a temperature between 0xc2x0 C. and room temperature, in the presence of a base such as triethylamine.
When using an isocyanate of formula (IIIc), the reaction is carried out in an inert solvent such as dichloromethane or benzene, at room temperature.
When using a carbamoyl chloride of formula (IIId), the reaction is carried out in a solvent such as toluene or 1,2-dichloroethane, at a temperature between 0xc2x0 C. and 110xc2x0 C., in the presence of a base such as triethylamine.
When using a sulfonyl chloride of formula (IIIe), the reaction is carried out in an inert solvent such as dichloromethane, in the presence of a base such as triethylamine, at a temperature between xe2x88x9220xc2x0 C. and room temperature.
In step 2) of the method or in step 2xe2x80x2) of the variant, the compound of formula (IV) or the compound of formula (XVII) thus obtained is deprotected, if appropriate, by the methods known to those skilled in the art. For example, when E is a tetrahydropyran-2-yl group, the deprotection is effected by acid hydrolysis using hydrochloric acid in a solvent such as ether, methanol or a mixture of these solvents, or using pyridinium p-toluenesulfonate in a solvent such as methanol, or else using an Amberlyst(copyright) resin in a solvent such as methanol, The reaction is carried out at a temperature between room temperature and the reflux temperature of the solvent. When E is a benzoyl group or a (C1-C4)alkylcarbonyl group, the deprotection is effected by hydrolysis in an alkaline medium using, for example, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide, in an inert solvent such as water, methanol, ethanol, dioxane or a mixture of these solvents, at a temperature between 0xc2x0 C. and the reflux temperature of the solvent.
In step 3) of the method or in step 3xe2x80x2) of the variant, the reaction of the alcohol of formula (V) or the alcohol of formula (XVIII) with a sulfonyl chloride of formula (VI) is carried out in the presence of a base such as triethylamine, pyridine, N,N-diisopropylethylamine or N-methylmorpholine, in an inert solvent such as dichloromethane, benzene or toluene, at a temperature between xe2x88x9220xc2x0 C. and the reflux temperature of the solvent.
In step 4) or in step 4xe2x80x2), the compound (VII) or the compound (XIX) thus obtained is reacted with a compound of formula (VIIIa), (VIIIb), (VIIIc), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VIIIi) or (VIIIj); in step 1xe2x80xa2), the compound (XIXxe2x80xa2) is reacted with a compound of formula (VIIIxe2x80xa2). The reaction is carried out in an inert solvent such as N,N-dimethylformamide, acetonitrile, methylene chloride, toluene, isopropanol or a mixture of these solvents, in the presence or absence of a base. When using a base, it is selected from organic bases such as triethylamine, N,N-diisopropylethylamine and N-methylmorpholine, or from alkali metal carbonates and bicarbonates such as potassium carbonate, sodium carbonate and sodium bicarbonate. In the absence of a base, the reaction is carried out using an excess of the compound of formula (VIIIa), (VIIIb), (VIIIc), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VIIIi), (VIIIj) or (VIIIxe2x80xa2) and optionally in the presence of an alkali metal iodide such as potassium iodide or sodium iodide. The reaction is carried out at a temperature between room temperature and 100xc2x0 C.
In step 5xe2x80x2) of the variant or in step 2xe2x80xa2), the compound of formula (XX) obtained or the compound of formula (XXxe2x80xa2) obtained is deprotected by the methods known to those skilled in the art.
The compounds of formula (I) according to the invention are finally obtained after deprotection of the hydroxyl groups or amino groups, if appropriate, or conversion of Xxe2x80x21 to X1, if appropriate.
The compounds of formula (I) or (Ixe2x80xa2) are isolated in the form of the free base or a salt by the conventional techniques.
Thus, when the compound of formula (I) or (Ixe2x80xa2) is obtained in the form of the free base, salification is effected by treatment with the chosen acid in an organic solvent. Treatment of the free base, dissolved for example in an ether such as diethyl ether, in an alcohol such as propan-2-ol, in acetone, in dichloromethane or in ethyl acetate, with a solution of the chosen acid in the same solvent gives the corresponding salt, which is isolated by the conventional techniques.
The hydrochloride, hydrobromide, sulfate, hydrogensulfate, dihydrogen-phosphate, methanesulfonate, oxalate, maleate, fumarate, naphthalene-2-sulfonate and benzenesulfonate, for example, are prepared in this way.
When the reaction has ended, the compounds of formula (I) or (Ixe2x80xa2) can be isolated in the form of one of their salts, for example the hydrochloride; in this case, if necessary, the free base can be prepared by neutralization of said salt with a mineral or organic base such as sodium hydroxide or triethylamine, or with an alkali metal carbonate or bicarbonate such as sodium or potassium carbonate or bicarbonate.
The compounds of formula (II) are obtained by known methods, particularly those described in patent applications EP-A-0 428 434, EP-A-0 474 561 and EP-A-O 512 901.
In particular, a compound of formula (II) in which R1 and R2 together form a group xe2x80x94(CH2)3xe2x80x94 and E is a hydrogen can be prepared according to SCHEME 1 below: 
In step 1, the reaction of a compound of formula (IX) with methyl acrylate, in the presence of a base such as Triton(copyright) B or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), gives the compound of formula (X). The reaction is carried out in an inert solvent such as 1,4-dioxane or tetrahydrofuran, at a temperature between 60xc2x0 C. and the reflux temperature of the solvent.
In step 2, the compound of formula (X) is hydrogenated in the presence of a catalyst such as Raney(copyright) nickel to give the compound of formula (XI). The reaction is carried out in an inert solvent such as an alkanol, preferably ethanol or 2-methoxyethanol, at a temperature between room temperature and 60xc2x0 C. and at a pressure between atmospheric pressure and 20 bar.
In step 3, the compound of formula (XI) is hydrolyzed in an alkaline medium using, for example, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, in a solvent such as water, methanol or a mixture of these solvents, at a temperature between room temperature and the reflux temperature of the solvent.
The resulting compound of formula (XII) is reduced in step 4 to give the expected compound of formula (II). The reduction is effected by means of a reducing agent such as lithium aluminum hydride, diisobutylaluminum hydride or borane in THF, in an inert solvent such as tetrahydrofuran, 1,2-dimethoxyethane or toluene, at a temperature between room temperature and the reflux temperature of the solvent.
In particular, a compound of formula (I) in which R1 and R2 together form a group xe2x80x94(CH2)4xe2x80x94 and E is the O-protecting group tetrahydropyran-2-yl (THP) can be prepared according to SCHEME 2 below: 
In step 1xe2x80x2 of SCHEME 2, a compound of formula (IX) is treated with a strong base, such as sodium hydride, lithium diisopropylamide or potassium tert-butylate, to give a carbanion, which is reacted with ethyl 4-bromobutanoate to give the compound of formula (XIII).
The reaction is carried out in an inert solvent such as an ether (for example tetrahydrofuran or 1,2-dimethoxyethane), an amide (for example N,N-dimethylformamide) or an aromatic hydrocarbon (for example toluene or xylene), at a temperature between xe2x88x9270xc2x0 C. and +60xc2x0 C.
In step 2xe2x80x2, the reaction of the compound of formula (XIII) with 2-(3-bromo-propoxy)tetrahydropyran, in the presence of a strong base such as sodium hydride, lithium diisopropylamide or potassium tert-butylate, under the operating conditions described in step 1xe2x80x2 above, gives the compound of formula (XIV).
The nitrile derivative of formula (XIV) is reduced in step 3xe2x80x2 to give the primary amine of formula (XV). The reduction is effected by means of hydrogen, in the presence of a catalyst such as Raney(copyright) nickel, in an inert solvent such as an alkanol, for example methanol, by itself or mixed with a saturated solution of ammonia in the same solvent, at a temperature between room temperature and 50xc2x0 C.
In step 4xe2x80x2, the cyclized compound of formula (XVI) is obtained by refluxing a solution of the compound of formula (XV) in an aromatic solvent such as toluene or xylene.
In step 5xe2x80x2, the compound of formula (XVI) is reduced to give the expected compound of formula (II). The reduction is effected by means of a reducing agent such as lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride or borane in THF, in an inert solvent such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane or toluene, at a temperature between room temperature and the reflux temperature of the solvent.
The compounds of formula (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe) or (IIIxe2x80xa2) are known or are prepared by known methods.
The piperidines of formula (VIIIa) are known or are prepared by known methods such as those described in EP-A-0 428 434, EP-A-0 474 561, EP-A-0512901 and EP-A-0 515240.
The piperidines of formula (VIIIa) can also be prepared by methods well known to those skilled in the art, such as those described in the following publications:
J. Heterocyclic Chem., 1986, 23, 73-75;
J. Chem. Soc., 1950, 1469;
J. Chem. Soc., 1945, 917;
J. Pharm. Sci., 1972, 61, 1316-1317;
J. Org. Chem., 1957, 22, 1484-1489;
Chem. Ber., 1975, 108, 3475-3482.
The compounds of formula (VIIIa) are generally prepared in a form protected on the piperidine nitrogen; the compounds of formula (VIIIa) themselves are obtained after a deprotection step.
Different methods of obtaining the compounds of formula (VIIIa), in which the different substituents are as defined for formula (I), unless stipulated otherwise, will be indicated below as examples.
For example, when Ar2 is a pyrid-2-yl group, Xxe2x80x21 is hydroxyl and x is zero in a piperidine of formula (VIIIa), 2-bromopyridine is reacted with N-benzylpiperid-4-one in a solvent, in the presence of butyllithium, in order to prepare N-benzyl-4-hydroxy-4-(pyrid-2-yl)piperidine; 4-hydroxy-4-(pyrid-2-yl)piperidine is then obtained by deprotection in a basic medium.
Furthermore, a compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94(CH2)mxe2x80x94OR4 in which R4 is hydrogen and m is one or two is prepared by reducing a compound of formula (VIIIa) in which Xxe2x80x21 is a methoxycarbonyl or, respectively, a methoxycarbonylmethyl by the method described in Chem. Ber., 1975, 108, 3475-3482.
A compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94(CH2)mxe2x80x94OR4 in which R4 is a (C1-C7)alkyl can also be prepared by alkylating a compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94(CH2)mxe2x80x94OH by the methods known to those skilled in the art.
A compound of formula (VIIIa) in which Xxe2x80x2hd 1 is a group xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94OR6 in which R6 is hydrogen can also be prepared by reacting a compound of formula (VIIIa) in which Xxe2x80x21 is a benzoyloxy- with ethylene glycol in the presence of an acid such as sulfuric acid.
The compounds of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94Oxe2x80x94CH2CH2xe2x80x94OR6 in which R6 is a (C1-C7)alkyl are prepared by an identical reaction using a 2-(C1 -C7)alkoxyethanol.
The compounds of formula (VIIIa) in which Xxe2x80x2hd 1 is a group xe2x80x94Oxe2x80x94CH2CH2xe2x80x94OR6 in which R6 is a formyl are prepared by reacting formic acid with a compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94Oxe2x80x94CH2CH2xe2x80x94OH. The compounds of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94Oxe2x80x94CH2CH2xe2x80x94OR6 in which R6 is a (C1-C7)-alkylcarbonyl are prepared by reaction with a C2-C8 acid chloride in the presence of a base such as triethylamine.
The compounds of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94(CH2)nxe2x80x94SR7 or a group xe2x80x94CH2xe2x80x94S(O)jxe2x80x94(C1-C7)alkyl are known or are prepared by known methods such as those described in WO 95/12577.
The compounds of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94(CH2)mxe2x80x94OCOR5 (R5 other than hydrogen) are prepared by reacting an acid chloride R5COCl (R5 other than hydrogen) with a compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94(CH2)mxe2x80x94OH, in the presence of a base such as triethylamine.
The compounds of formula (VHIa) in which Xxe2x80x21 is a group xe2x80x94(CH2)mxe2x80x94OCOR5 in which R5 is hydrogen are prepared by reacting formic acid with a compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94(CH2)mxe2x80x94OH.
The compounds of formula (VIIIa) in which Xxe2x80x21 is a group (C1-C7)alkyl-NHCOOxe2x80x94(CH2)mxe2x80x94 are obtained by reacting a carbamoyl chloride, (C1-C7)alkyl-NHCOCl, with the compounds of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94(CH2)mxe2x80x94OH. The same compounds are prepared by reacting an isocyanate, (C1-C7)alkyl-Nxe2x95x90Cxe2x95x90O, with the compounds of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94(CH2)mxe2x80x94OH.
The compounds of formula (VIIIa) in which Xxe2x80x21 is a hydroxyl and which carry a protecting group on the piperidine nitrogen can undergo a Ritter reaction with acetonitrile in order to prepare the compounds of formula (VIIIa) in which Xxe2x80x21 is an acetamido. The compounds of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94NR8R9 in which R8 and R9 are each hydrogen are then prepared by hydrolysis in an acid medium.
A compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94NR8R9 in which R8 and R9 are each hydrogen can also be prepared by hydrolyzing in a strong acid medium, for example hydrochloric acid, a compound of formula (VIIIa) in which Xxe2x80x21 is an isocyanato group.
A compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94NR8R9 in which R8 is hydrogen and R9 is a (C1-C7)alkyl, or a (C3-C7)cycloalkylmethyl or a benzyl, can be prepared by reducing a compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94NR12COR13 in which R12 is hydrogen and R13 is a hydrogen or a (C1-C6)alkyl or, respectively, a (C3-C7)cycloalkyl or a phenyl. The reaction is carried out by means of a reducing agent such as lithium aluminum hydride, in a solvent such as tetra-hydrofuran, at the reflux temperature of the solvent.
The compounds of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94NR8R9 in which R8 is a (C1-C7)alkyl can be prepared by an identical reaction from the compounds of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94NR12COR13 in which R12 is a (C1-C7)alkyl.
A compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94NR8R9 in which R8 and R9, together with the nitrogen atom to which they are bonded, form a hetero-cycle is prepared by applying or adapting Bruylants"" reaction (Bull. Soc. Chim. Belges, 1924, 33 467, and Tetrahedron Letters, 1988, 29 (52), 6827-6830).
A compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94CH2xe2x80x94NR10R11 in which R10 and R11 are each hydrogen is prepared by reducing a compound of formula (VIIIa) in which Xxe2x80x21 is a cyano. This reduction is effected by the methods well known to those skilled in the art.
A compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94CH2xe2x80x94CH2xe2x80x94NR1OR11 in which R10 and R11 are each a hydrogen is prepared from a compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94CH2xe2x80x94CH2xe2x80x94OH by applying or adapting the method described in J. Med. Chem., 1989, 32, 391-396.
The compounds of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94(CH2)pxe2x80x94NR1OR11 in which R10 is a hydrogen or a (C1-C7)alkyl and R11 is a (C1-C7)alkyl, a (C3-C7)-cycloalkylmethyl or a benzyl can be prepared by reducing a compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94(CH2)pxe2x80x94NR14C(xe2x95x90W1)R16 in which R14 is a hydrogen or a (C1-C7)alkyl, R16 is a hydrogen, a (C1-C6)alkyl, a (C3-C7)cycloalkyl or a phenyl and W1 is an oxygen atom.
The compounds of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94NR12COR13 in which R12 is a hydrogen or a (C1-C7)alkyl and R13 is hydrogen or respectively a (C1-C7)alkyl, an optionally substituted (C3-C7)cycloalkyl, a phenyl, a benzyl, a vinyl, a pyridyl, a furyl, a thienyl, a pyrrolyl or an imidazolyl are obtained by reacting formic acid in acetic anhydride or, respectively, an appropriate acid chloride R13COCl, in the presence of a base such as triethylamine, with a compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94NHR12. In particular, a compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94NR12COR13 in which R13 is an ethyl radical can be prepared by hydrogenating, in the presence of a catalyst such as palladium on charcoal, a compound of formula (VIIIa) in which Xxe2x80x21 is an acryloylamino or acryloyl-N-(C1-C7)alkylamino group.
A compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94NR12COR13 in which R12 and R13 together are a group xe2x80x94(CH2)3xe2x80x94 or xe2x80x94(CH2)4xe2x80x94 is prepared by applying or adapting the method described in J. Med. Chem., 1985, 28, 46-50.
A compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94NR14COCOR15 in which R15 is a (C1-C4)alkoxy is prepared by reacting a compound of the formula Clxe2x80x94COCOR15 with a compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94NHR14.
The compounds of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94(CH2)pxe2x80x94NR14C(xe2x95x90W1)R16 in which W1 is an oxygen atom, p is 1 or 2, R14 is a hydrogen or a (C1-C7)alkyl and R16 is a hydrogen or respectively a (C1-C7)alkyl, a phenyl, a benzyl, a pyridyl, an optionally substituted (C3-C7)cycloalkyl, a vinyl, a furyl, a thienyl, a pyrrolyl or an imidazolyl are obtained by reacting formic acid in acetic anhydride or, respectively, an appropriate acid chloride R16COCl, in the presence of a base such as triethylamine, with a compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94CH2xe2x80x94NHR14 or xe2x80x94CH2xe2x80x94CH2xe2x80x94NHR14.
A compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94(CH2)pxe2x80x94NR14C(xe2x95x90W1)R16 in which W1 is a sulfur atom is obtained from a corresponding compound of formula (VIIIa) which is protected on the piperidine nitrogen and in which W1 is an oxygen atom by reaction with phosphorus pentasulfide or with Lawesson""s reagent, 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-disphosphetane-2,4-disulfide, followed by deprotection of the piperidine nitrogen.
A compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94(CH2)mxe2x80x94NR14COOR17 is prepared by reacting a chloroformate of the formula ClCOOR17 with a compound of formula (VIIIa) in which Xxe2x80x21 is a group (CH2)mNHR14, in the presence of a base such as triethylamine.
It is also possible to prepare a compound of formula (VIIIa) in which Xxe2x80x21 is a group (CH2)mxe2x80x94NR14COOR17 in which m=0 and R14 is hydrogen by reacting a compound R17OH with a compound of formula (VIIIa) in which Xxe2x80x21 is an isocyanato group (xe2x80x94Nxe2x95x90Cxe2x95x90O).
A compound of formula (VIIIa) in which Xxe2x80x21 is an isocyanato group is prepared from a compound of formula (VIIIa) in which Xxe2x80x21 is a carboxyl group by the method described in Organic Synthesis, 51, 48-52.
A compound of formula (VIIIa) in which Xxe2x80x21 is a group (CH2)mxe2x80x94NR14SO2R18 is prepared by reacting a sulfonyl chloride ClSO2R18 with a compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94(CH2)mxe2x80x94NHR14, in the presence of a base such as triethylamine.
Likewise, the compounds of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94(CH2)mxe2x80x94NR14CONR19R20 in which R19 is a hydrogen and R20 is a (C1-C7)alkyl are prepared by reaction with an isocyanate of the formula R20Nxe2x95x90Cxe2x95x90O in which R20 is a (C1-C7)alkyl.
The compounds of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94(CH2)mxe2x80x94Nxe2x80x94R14CONR19R20 in which R19 is a (C1-C7)alkyl are prepared by reaction with a carbamoyl chloride of the formula ClCONR19R20.
A compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94(CH2)mxe2x80x94NR14CONR19R20 can also be obtained by reacting a compound HNR19R20 with a compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94(CH2)mxe2x80x94NR14COOR17 in which R17 is a phenyl.
A compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94(CH2)mxe2x80x94NR14CONR19R20 in which m=0 and R14 is hydrogen can also be prepared by reacting a compound NHR19R20 with a compound of formula (VIIIa) in which Xxe2x80x21 is an isocyanato group.
A compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94(CH2)mxe2x80x94NR14C(xe2x95x90W1)NR19R20 in which W1 is a sulfur atom is prepared by reacting a compound of formula (VIIIa), protected on the piperidine nitrogen, in which Xxe2x80x21 is a group xe2x80x94(CH2)mxe2x80x94NR14CONR19R20 with phosphorus pentasulfide or with Lawesson""s reagent.
A compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94CONR19R20 is prepared by reacting a compound of formula (VIIIa) in which Xxe2x80x21 is a carboxyl with a compound of formula HNR19R20 by the methods well known to those skilled in the art.
Likewise, the compounds of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94CH2xe2x80x94CONR19R20 are prepared by reacting a compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94CH2xe2x80x94COOR2 in which R21 is hydrogen with a compound HNR19R20.
A compound of formula (VIIIa) in which Xxe2x80x21 is a group (CH2)nxe2x80x94C(xe2x95x90W1)NR19R20 in which W1 is a sulfur atom is prepared, by the above-mentioned methods, from a compound of corresponding formula (VIIIa) in which W1 is an oxygen atom.
A compound of formula (VIIIa) in which Xxe2x80x21 is a carboxyl can be prepared by hydrolyzing a compound of formula (VIIIa) in which Xxe2x80x21 is a cyano by the methods known to those skilled in the art.
A compound of formula (VIIIa) in which Xxe2x80x21 is a carboxymethyl can be prepared by the method described in Chem. Ber., 1975, 108, 3475-3482.
A compound of formula (VIIIa) in which Xxe2x80x21 is a (C1-C7)alkoxycarbonyl or a (C1-C7)alkoxycarbonylmethyl can be prepared from a compound of formula (VIIIa) in which Xxe2x80x21 is a carboxyl or, respectively, a carboxymethyl by means of an esterification reaction by the methods well known to those skilled in the art.
In particular, a compound of formula (VIIIa) in which Ar2 is an optionally substituted phenyl radical, x is one and Xxe2x80x21 is a (C1-C7)alkoxycarbonyl is prepared by reacting a protected 4-(C1-C7)alkoxycarbonylpiperidine with an optionally substituted benzyl halide in the presence of a base such as sodium hydride, potassium tert-butylate or sodium diisopropylamide, in a solvent such as tetra-hydrofuran, N,N-dimethylformamide or dimethyl sulfoxide, at a temperature between xe2x88x9278xc2x0 C. and room temperature. The expected compound of formula (VIIIa) is obtained after a deprotection step.
A compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94COxe2x80x94NR22xe2x80x94NR23R24 is prepared by reacting a hydrazine HNR22xe2x80x94NR23R24 with a compound of formula (VIIIa) in which Xxe2x80x21 is a chloroformyl.
A compound of formula (VIIIa) in which Xxe2x80x21 is a group 
in which R26 and R27 are each independently a hydrogen or a (C1-C7)alkyl is prepared by reacting a compound of formula (VIIIa) in which Xxe2x80x21 is a group 
in which Hal is a halogen atom, preferably bromine, with a thiourea in which one of the amino groups is free or substituted by one or two (C1-C7)alkyls.
A compound of formula (VIIIa) in which Xxe2x80x21 is a group 
in which R27 is a formyl or respectively a (C1-C7)alkylcarbonyl is prepared by reacting formic acid in acetic anhydride or, respectively, an acid chloride (C1-C7)alkyl-COCl, in the presence of a base such as triethylamine, with the above compound of formula (VIIIa), protected on the piperidine nitrogen, in which R27 is hydrogen. The expected compound is obtained after a deprotection step.
The compound of formula (VIIIa) in which Xxe2x80x21 is a group 
in which Hal is a bromine atom is obtained by the bromination, by the conventional methods, of a compound of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94COxe2x80x94CH2xe2x80x94R25.
A compound of formula (VIIIa) in which Xxe2x80x21 is a group 
can be prepared by reacting a protected compound of formula (VIIIa) in which Xxe2x80x21 is a carbazoyl group (xe2x80x94CONHxe2x80x94NH2) with cyanogen bromide by the method described in J. Org. Chem., 1961, 26, 88-95. The compound of formula (VIIIa) in which Xxe2x80x21 is a carbazoyl group is obtained by reacting hydrazine with a compound of formula (VIIIa) in which Xxe2x80x21 is a chloroformyl, which is itself obtained by reacting thionyl chloride with a compound of formula (VIIIa) in which Xxe2x80x21 is a carboxyl.
The piperazines of formula (VIIIb) are known or are prepared by known methods such as those described in EP-A-0 428 434.
The piperidines of formula (VIIIc) are known or are prepared by known methods such as those described in WO 94/10146.
The piperidines of formula (VIIId) are known or are prepared by known methods such as those described in EP-A-0 625 509.
The piperidines of formula (VIIIe) are known or are prepared by known methods such as those described in EP-A-0 630 887.
The piperidines of formula (VIIIf) are known or are prepared by known methods such as those described in WO 94/26735.
The compounds of formula (VIIIg) are known or are prepared by known methods such as those described in WO 94/29309.
The piperidines of formula (VIIIh) are known or are prepared by known methods such as those described in WO 95/05377.
The piperidines of formula (VIIIi) are known or are prepared by known methods such as those described in WO 95/12577.
The piperidines of formula (VIIIj) are known or are prepared by known methods.
In particular, the piperidines of formula (VIIIj) in which Jxe2x80x26 is a group 
in which Xxe2x80x21 is other than hydrogen and W25 is a (C1-C7)alkyl or a (C3-C7)cycloalkyl are prepared by the procedures described above for the preparation of the piperidines of formula (VIIIa).
A piperidine of formula (VIIIj) in which Jxe2x80x26 is a group 
in which W25 is a group xe2x80x94NR79R80 and Xxe2x80x21 is a cyano is prepared by means of a Strecker reaction between a 1-benzylpiperid-4-one and a compound of the formula NHR79R80 in the presence of sodium cyanide. The compound of expected formula (VIIIj) is obtained after a deprotection step. Hydrolysis of the cyano group in a strong medium by the methods known to those skilled in the art gives the corresponding piperidines of formula (VIIIj) in which Xxe2x80x21 is a carboxyl. The latter compounds can be used to obtain the corresponding piperidines of formula (VIIIj) in which Xxe2x80x21 is a (C1-C7)alkoxycarbonyl or a group xe2x80x94CONR19R20 by the methods known to those skilled in the art, for example by means of esterification or, respectively, by the methods of peptide coupling.
The piperidines of formula (VIIIxe2x80xa2) are also known or can be prepared by known methods. In particular, when Jxe2x80xa2 is a group of the structure 
the piperidine of formula (VIIIxe2x80xa2) is prepared by one of the methods described above for the compounds of formula (VIIIa) in which Xxe2x80x21 is a group xe2x80x94CONR19R20, especially by reacting a carboxylic acid of the formula 
with an amine of the formula NHR19R20.
When Jxe2x80xa2 is a group of the structure 
the piperidine of formula (VIIIxe2x80xa2) is prepared by methods described in WO 94/29309.
The enantiomers of the compounds according to the invention, of the formula 
in which:
xe2x80x9c*xe2x80x9d denotes that the carbon atom carrying this label has the determined (+) or (xe2x88x92) absolute configuration; and
R1, R2, Ar1, T, A, Z and B are as defined for the compounds of formula (I), and their salts with mineral or organic acids, are novel compounds which form part of the invention.
The enantiomers of formula (I*) can be isolated by resolution of the racemic mixtures of the compounds of formula (I). It is preferable, however, to resolve the racemic mixtures at the stage of an intermediate which can be used to prepare a compound of formula (I), as described in patent applications EP-A-0 474 561, EP-A-0 512 901, EP-A-0 591 040 and EP-A-0 612 716.
The compounds of formula (I) above also include those in which one or more hydrogen, carbon or iodine atoms have been replaced by their radioactive isotope, for example tritium, carbon 14 or iodine 125. Such labeled compounds are useful in research, metabolic or pharmacokinetic studies and in biochemical assays as receptor ligands.
The affinity of the compounds of formula (I) for the tachykinin receptors was evaluated in vitro by means of several biochemical assays using radioligands:
1xe2x80xa2) The binding of [125I]BH-SP (substance P labeled with iodine 125 using Bolton-Hunter""s reagent) to the NK1 receptors of rat cortex, guinea-pig ileum and human lymphoblastic cells.
2xe2x80xa2) The binding [125I]His-NKA to the NK2 receptors of rat bladder or the binding [125I]NPxcex3 to the NK2 receptors of guinea-pig ileum.
3xe2x80xa2) The binding [125I]His[MePhe7]NKB to the NK3 receptors of rat cerebral cortex, guinea-pig cerebral cortex and gerbil cerebral cortex and to the human NK3 cloned receptors expressed by CHO cells (Buell et al., FEBS Letters, 1992, 299, 90-95).
The assays were performed according to X. Emonds-Alt et al. (Eur. J. Pharmacol., 1993, 250, 403-413).
The compounds according to the invention strongly inhibit the binding of [125I]His[MePHe7]NKB to the NK3 receptors of guinea-pig and gerbil cerebral cortex and to the human NK3 cloned receptors: the inhibition constant Ki is generally less than 5.10xe2x88x929 M. For the same compounds, it was found that the inhibition constant (Ki) for the NK3 receptors of rat cerebral cortex is generally greater than 10xe2x88x929 M and that the inhibition constant (Ki) for the NK2 receptor of rat duodenum and the NK1 receptors of rat cortex is generally greater than or equal to 10xe2x88x927 M.
The compounds according to the present invention were also evaluated in vivo on two animal models.
In the gerbil, a rotational behavior is induced by the intrastriatal administration of the specific NK3 receptor agonist senktide; it was found that a unilateral administration of senktide to gerbil striatum leads to strong contralateral rotations which are inhibited by the compounds according to the invention, administered either intraperitoneally or orally.
This result shows that the compounds according to the invention pass through the blood-brain barrier and that they are capable of blocking the characteristic action of the NK3 receptors in the central nervous system. They may thus be used for the treatment of any NKB-dependent pathological condition of the central nervous system, such as psychiatric diseases, or any pathological condition mediated by the NK3 receptor in the central nervous system, such as psychosomatic diseases.
In the guinea-pig, an intravenous or intracerebroventricular injection of senktide induces hypertension which is suppressed by the oral or intravenous administration of the compounds according to the invention.
This result shows that the compounds according to the invention act on the cardiovascular system and that they are capable of blocking the characteristic action of the NK3 receptors in said system, especially hypertension (Nakayama et al., Brain Res., 1992, 595, 339-342; Takano and Kamiya, Asia Pacific J. Pharmacol., 1991, 6, 341-346; Saigo et al., Neuroscience Letters, 1993, 159, 187-190).
In the guinea-pig, the inhalation of substance P, for example, induces bronchial hyperreactivity to acetylcholine and hypersensitivity to histamine, for example in the plasmic extravasation. An NK3 antagonist blocks these two characteristic processes of respiratory pathological conditions like asthma.
In these tests, the compounds according to the invention are active at doses varying from 0.1 mg to 30 mg per kg, administered orally, intravenously or intraperitoneally.
The compounds of the present invention are generally administered in dosage units. Said dosage units are preferably formulated into pharmaceutical compositions in which the active principle is mixed with a pharmaceutical excipient.
According to another of its aspects, the present invention relates to pharmaceutical compositions containing, as the active principle, a compound of formula (I) or one of its pharmaceutically acceptable salts which has a very high affinity for the human NK3 receptor, said affinity being characterized by an inhibition constant Ki generally of less than 5.10xe2x88x929 M in ligand binding studies.
The compounds of formula (I) and their pharmaceutically acceptable salts can be used in daily doses of 0.01 to 100 mg per kilogram of body weight of the mammal to be treated, preferably in daily doses of 0.1 to 50 mg/kg. In humans the dose can preferably vary from 0.5 to 4000 mg per day, more particularly from 2.5 to 1000 mg, depending on the age of the subject to be treated or the type of treatment: prophylactic or curative.
Examples of diseases which can be treated using the compounds and their pharmaceutically acceptable salts are diseases associated with a dysfunction of the dopaminergic systems, such as schizophrenia and Parkinson""s disease, diseases associated with a dysfunction of the noradrenergic and serotoninergic systems, such as anxiety, vigilance disorders and humor disorders, all forms of epileptic disease, particularly grand mal, dementia, neurodegenerative diseases, peripheral diseases in which the central nervous system and/or the peripheral nervous system participate via neurokinin B acting as a neurotransmitter or neuromodulator, such as pain, migraine and acute or chronic inflammation, cardiovascular disorders, particularly hypertension, cardiac insufficiency and rhythm disorders, respiratory disorders (asthma, rhinitis, cough, bronchitis, allergy, hypersensitivity), disorders of the gastrointestinal system, such as esophageal ulcer, colitis, stress-related disorders, irritable bowel syndrome (IBS) and acidic secretion, emesis/nausea (following chemotherapy, postoperative, due to travel sickness or due to vestibular disorders), disorders of the urinary system (incontinence, nervous bladder), diseases of the immune system (rheumatoid arthritis) and, more generally, any neurokinin B-dependent pathological condition.
In the pharmaceutical compositions of the present invention for oral, sublingual, inhalational, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active principles can be administered to animals and humans in unit forms of administration, mixed with conventional pharmaceutical carriers. The appropriate unit forms of administration include forms for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual and buccal administration, forms for subcutaneous, intramuscular, intravenous, intranasal or intraocular administration and forms for rectal administration.
When a solid composition in the form of tablets is prepared, the main active principle is mixed with a pharmaceutical vehicle such as silica, gelatin, starch, lactose, magnesium stearate, talcum, gum arabic or the like. The tablets can be coated with sucrose various polymers or other appropriate substances or else they can be treated so as to have a sustained or delayed activity and so as to release a predetermined amount of active principle continuously.
A preparation in the form of gelatin capsules is obtained by mixing the active principle with a diluent, such as a glycol or a glycerol ester, and introducing the mixture obtained into soft or hard gelatin capsules.
A preparation in the form of a syrup or elixir can contain the active principle together with a sweetener, which is preferably calorie-free, methylparaben and propylparaben as antiseptics, a flavoring and an appropriate color.
The water-dispersible granules or powders can contain the active principle mixed with dispersants or wetting agents or with suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors.
Rectal administration is effected using suppositories, which are prepared with binders melting at the rectal temperature, for example cocoa butter or polyethylene glycols.
Parenteral, intranasal or intraocular administration is effected using aqueous suspensions, isotonic saline solutions or injectable solutions which contain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol or butylene glycol.
Administration by inhalation is effected using an aerosol which also contains, for example, sorbitan trioleate or oleic acid, as well as trichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethane or any other biologically compatible propellant gas; it is also possible to use a system containing the active principle, by itself or in association with an excipient, in powder form.
The active principle can also be presented in the form of a complex with a cyclodextrin, for example xcex1-, xcex2- or xcex3-cyclodextrin, 2-hydroxypropyl-xcex2-cyclodextrin or methyl-xcex2-cyclodextrin.
The active principle can also be formulated as microcapsules, with one or more carriers or additives if appropriate.
In each dosage unit, the active principle of formula (I) is present in the amounts commensurate with the daily doses envisaged. In general, each dosage unit is appropriately adjusted according to the dosage and the intended type of administration, for example tablets, gelatin capsules and the like, sachets, ampoules, syrups and the like, or drops, so that said dosage unit contains from 0.5 to 1000 mg of active principle, preferably from 2.5 to 250 mg, for administration one to four times a day.
The above-mentioned compositions can also contain other active products which are useful for the desired therapeutics, such as, for example, bronchodilators, antitussives or antihistamines.
By virtue of their very high affinity for the human NK3 receptor and their high selectivity, the compounds according to the invention may be used in radio-labeled form as laboratory reagents.
For example, they make it possible to characterize, identify and locate the human NK3 receptor in tissue sections or the NK3 receptor in the whole animal by autoradiography.
The compounds according to the invention also make it possible to sort or screen molecules as a function of their affinity for the human NK3 receptor. This is carried out by means of a reaction in which the radiolabeled ligand forming the subject of the present invention is displaced from its human NK3 receptor.
The following abbreviations are used in the Preparations and in the